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3G study protocol

Summary Background Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. Methods Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov , NCT03033446 and has been completed. Findings 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4–48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3–4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). Interpretation Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. Funding National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.

PURPOSE Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.

Gastric cancer cases are often diagnosed at an advanced stage with poor prognosis. Platinum-based chemotherapy has been internationally accepted as first-line therapy for inoperable or metastatic gastric cancer. To achieve greater benefits, selection of patients eligible for this treatment is critical. Although gene expression profiling has been widely used as a genomic classifier to identify molecular subtypes of gastric cancer and to stratify patients for different chemotherapy regimens, its prediction accuracy can be improved. Adenosine-to-inosine (A-to-I) RNA editing has emerged as a new player contributing to gastric cancer development and progression, offering potential clinical utility for diagnosis and treatment. Using a systematic computational approach followed by both in vitro validations and in silico validations in The Cancer Genome Atlas (TCGA), we conducted a transcriptome-wide RNA editing analysis of a cohort of 104 patients with advanced gastric cancer and identified an RNA editing (GCRE) signature to guide gastric cancer chemotherapy. RNA editing events stood as a prognostic and predictive biomarker in advanced gastric cancer. A GCRE score based on the GCRE signature consisted of 50 editing sites associated with 29 genes, predicting response to chemotherapy with a high accuracy (84%). Of note, patients demonstrating higher editing levels of this panel of sites presented a better overall response. Consistently, gastric cancer cell lines with higher editing levels showed higher chemosensitivity. Applying the GCRE score on TCGA dataset confirmed that responders had significantly higher levels of editing in advanced gastric cancer. Overall, this newly defined GCRE signature reliably stratifies patients with advanced gastric cancer and predicts response from chemotherapy. Significance: This study describes a novel A-to-I RNA editing signature as a prognostic and predictive biomarker in advanced gastric cancer, providing a new tool to improve patient stratification and response to therapy.

Summary Background Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. Methods CP-MGAH22–05 was a single-arm, open-label, phase 1b–2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov , NCT02689284 . Recruitment for the trial has completed and follow-up is ongoing. Findings Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7–23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3–4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15–27·93) of 92 evaluable patients. Interpretation These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). Funding MacroGenics.

PURPOSE Concurrent PIK3CA mutations and fibroblast growth factor receptor (FGFR) alterations occur in multiple cancer types, including estrogen receptor–positive breast cancer, bladder cancer, and endometrial cancer. In this first-in-human combination trial, we explored safety and preliminary efficacy of combining the PI3Kα selective inhibitor alpelisib with the FGFR1-4 selective inhibitor infigratinib. PATIENTS AND METHODS Patients with PIK3CA-mutant advanced solid tumors, with or without FGFR1-3 alterations, were enrolled in the dose escalation or one of three molecular-defined dose-expansion cohorts. The primary end point was the maximum tolerated dose. Secondary end points included safety, pharmacokinetics, and response. Archival tumor samples were sequenced to explore genomic correlates of response. RESULTS In combination, both agents were escalated to full, single-agent recommended doses (alpelisib, 300 mg per day continuously; infigratinib, 125 mg per day 3 weeks on followed by 1 week off). The toxicity profile of the combination was consistent with the established safety profile of each agent, although 71% of all patients required at least one treatment interruption or dose reduction. Molecularly selected dose expansions in breast cancer and other solid tumors harboring PIK3CA mutations, alone or in combination with FGFR alterations, identified sporadic responses, predominately in tumor types and genotypes previously defined to have sensitivity to these agents. CONCLUSION The combination of alpelisib and infigratinib can be administered at full single-agent doses, although the high rate of dose interruption or reduction suggests long-term tolerability may be challenging. In exploratory signal-seeking cohorts of patients harboring dual PIK3CA and FGFR1-3 alterations, no clear evidence of synergistic activity was observed.

The COVID-19 pandemic has affected the conduct of clinical trials in an unparalleled manner due to multiple levels of restrictions imposed to control the spread of SARS-CoV2. These restrictions have presented major challenges for clinicians, sponsors, contract research organizations and patients participating in ongoing clinical trials and have necessitated alternative solutions to ensure study and patient care continuity. In this review, we assessed the impact of the pandemic on key metrics of the commencement and continuation of clinical trials in the Asia-Pacific region and the efforts made to mitigate these challenges. Overall, newly initiated studies in 2020, outside of those directly related to COVID-19, were reduced. Access to sites and recruitment were also impacted significantly although recovery has begun in the latter half of 2020. Clinical trials consist of complex workflows across study procedures and site-patient engagements. Based on clinician and industry surveys, the impact of COVID-19 may drive an increase in interest and adoption of virtual, digital technologies and tools to help alleviate the numerous challenges for clinical trial stakeholders. We discuss these new approaches and debate their readiness and appropriateness for widespread use. With ongoing acceleration of the pandemic and the maturation of technology, we expect increasing near-term adoption of virtual and digital methodologies in clinical trials. As a silver lining of the pandemic, these approaches may make studies more patient centric, improve clinical trial efficiency and enhance the experience and care of the patients enrolled on trials.

Aim The significance and prioritization of early phase oncology trial continuation during a global pandemic is unknown. This study reported the outcomes, multiple challenges, and broad recommendations associated with the impact of the novel coronavirus disease 2019 (COVID‐19) on oncology early phase 1 trials—and on drug development in Asia—based on the experiences and perspectives of Asian oncology phase 1 centers. Methods Between March and April 2020 during the initial period of outbreak, the impact of COVID‐19 across oncology phase 1 sites in five Asian countries—China (Hong Kong), Japan, South Korea, Taiwan, and Singapore—was retrospectively analyzed. Results There was no trial termination or treatment discontinuation in all five countries. Although the most common impact was new patient enrollment being placed on hold, which was based on pharmaceutical sponsors’ decision‐making, the situation varied per site. Most sites had no restrictions in place that would limit their ability to fully comply with the requirements of conducting the early phase studies. The number of protocol deviations during the pandemic was largely dependent on domestic transportation status during the outbreak rather than the ability of the clinical trial centers. Conclusion Determining the risk to benefits ratio of patients with cancer who are enrolled in early phase 1 clinical trials under the unusual circumstances of a global pandemic is important. Specific guidance or guidelines on the conduct of early phase 1 clinical trials during public health emergencies that are based on the recent lessons learned is urgently required., First detailed report of the impact of COVID‐19 across oncology phase 1 sites in five Asian countries—China (Hong Kong), Japan, South Korea, Taiwan, and Singapore between March and April 2020 during the midst of pandemic. ‐ There was no trial termination or treatment discontinuation in all five countries. ‐ Most sites had no restrictions in place that would limit their ability to fully comply with the requirements of conducting the early phase 1 studies.

Proposed short titleY90-Resin Microspheres Radioembolization Followed by Nivolumab in Advanced Hepatocellular CarcinomaBackground : Nivolumab (N) and Y90-resin microspheres radioembolization (Y90-RE) aretherapeutic options in advanced hepatocellular carcinoma (aHCC). Emerging evidence suggests synergy between radiotherapy and immune checkpoint inhibitors. Methods : Eligible Child-Pugh A aHCC patients were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies were obtained. Primary end-point was overall response rate (ORR) (RECIST v1·1), defined as the composite overall response observed for lesions both within and outside Y90-RE field. Secondary end points included progression free survival (PFS), overall survival (OS), and safety. This study is registered with ClinicalTrials.gov, NCT03033446 .Findings : Forty patients were enrolled, 36 received Y90-RE followed by N. At baseline: 61·1% had hepatitis B; 66·7% BCLC stage C; 50·0% had AFP > 400ng/mL; median number of liver lesions was 5 (range 1- >20); median size of largest liver lesion was 78·5 mm (range 14-177mm); 38·9% had prior TACE/RFA/MWA; and 12·5% had prior systemic therapy. ORR was 30·6% (16·4% to 48·1%). ORR was 43·5% in patients with no extra-hepatic spread (EHS) (n=23). 81% of target lesions within Y90-RE field regressed. Median PFS and OS were 5·6 months (95% CI 2·1 to 8·8 months) and 16.9 months (95% CI 8·1 to 27·6 months). Treatment was well tolerated with only 13·8% experiencing grade (G) 3/4 treatment related adverse events (TRAEs). Immune activation predicted response to Y90-RE followed by N. Interpretation : Y90-RE followed by N resulted in an encouraging ORR of 30·6% in aHCC and of 43·5% in subjects with no EHS. 81% of target lesions within Y90-RE field regressed suggesting synergy. Importantly, this combination is safe and tolerable with low G 3/4 TRAEs of 13·8%. Trial Registration: NCT number: NCT03033446 Funding: Funding for this study was acquired from National Medical Research Council Singapore (NMRC/CIRG/1454/2016), Bristol-Myers Squibb (BMS), and SIRTEX Declaration of Interest: David Tai All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): BMS, SIRTEX, NMRC Singapore (CIRG/1470/2017) Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: IPSEN, Eisai, BMS Consulting fees: Novartis, BMS, MSD Choo Su Pin Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, BMS, Ipsen, Lilly, AZ, Roche. Consulting fees: BMS, Roche, Ipsen, Servier, Eisai, AstraZeneca. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: MOH Medishield Life Cancer Drug committee Stock or stock options: BMS David Ng All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): SIRTEX Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Joycelyn Lee Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, IPSEN, Bayer Research Funding: Bayer Pierce K.H. Chow Grants or contracts from any entity: Sirtex Medical, Ipsen, IQVIA, New B Innovation, Perspectum, AMiLi, MiRXES, Genentech, Engine Biosciences. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sirtex Medical, Ipsen, Oncosil, Bayer, Roche, New B Innovation, MSD, BTG PLC, Eisai, Abbott, AZ, IQVIA, Genentech, Worrell Guerbet, LEK Consulting, COR2ED. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: AVATAMED Stock or stock options: AVATAMED Too Chow Wei Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Consulting fees: SIRTEX Ethical Approval: All patients provided written informed consent and the institutional review board committee approved the protocol (Singhealth IRB Ref No. 2016/2613). The study was done in accordance with the Declaration of Helsinki and Good Clinical Practice.

Purpose: The oxaliplatin plus S-1 and cisplatin plus S-1 regimens are interchangeably used in the management of advanced gastric cancer. The previously reported G-intestinal (G1) and G-diffuse (G2) intrinsic gene expression signatures showed promise for stratifying patients according to their tumor sensitivity to oxaliplatin or cisplatin. Experimental Design: The proof-of-concept, multicenter, open-label phase II “3G” trial was done to prospectively evaluate the feasibility and efficacy of using genomic classifiers to tailor treatment in gastric cancer. Patients’ tumors were classified as “G1” or “G2” using a nearest-prediction template method, or “G3” (unclear assignment) when FDR ≥ 0.05. The first 30 patients in the “G1” cohort were assigned oxaliplatin plus S-1 (SOX) chemotherapy; thereafter, subsequently recruited “G1” patients were treated with cisplatin plus S-1 (SP) chemotherapy. “G2” patients and “G3” patients were treated with SP and SOX chemotherapy, respectively. Results: A total of 48, 21, and 12 patients, respectively, were given “G1,” “G2,” and “G3” genomic assignments. Median turnaround time was 7 days (IQR, 5–9). Response rates were 44.8%, 8.3%, 26.7%, and 55.6% for the “G1-SOX,” “G1-SP,” “G2,” “G3” cohorts, respectively; and was higher in G1 patients treated with SOX compared with SP (P = 0.033). Exploratory analyses using the genomic classifier of Lei and colleagues validated the utility of the metabolic signature as a biomarker for predicting benefit from chemotherapy (log-rank P = 0.004 for PFS), whereas the Asian Cancer Research Group classifier did not demonstrate any predictive value. Conclusions: This bench-to-bedside effort establishes a reasonable turnaround time for gene expression profiling and possible utility of genomic classifiers in gastric cancer treatment stratification. Clin Cancer Res; 24(21); 5272–81. ©2018 AACR.

BACKGROUND Metastatic gastric cancer has a poor prognosis. We aim to study how clinical features and prognosis differs between different metastatic sites, and to identify prognostic factors for overall survival. METHODS We retrospectively reviewed patients with metastatic gastric adenocarcinoma managed at a tertiary referral cancer center over a 5-year period. We divided our cohort into three groups based on the site(s) of metastasis at presentation-peritoneal metastasis only (P), distant metastasis only (D), and peritoneal and distant metastases (PD). RESULTS We studied 470 patients with 175 (37.2%), 193 (41.1%) and 102 (21.7%) patients in the P, D and PD groups, respectively. Patients with peritoneal disease (both P and PD) had higher proportions of patients experiencing chemotherapy disruption due to unplanned hospitalizations, which were also of a longer average duration. The P group had the longest overall median survival of 8.9 months compared to the PD and D groups with 7.4 and 5.5 months, respectively (P

AIM To characterize patients with gastric peritoneal carcinomatosis (PC) and their typical clinical and treatment course with palliative systemic chemotherapy as the current standard of care. METHODS We performed a retrospective electronic chart review of all patients with gastric adenocarcinoma with PC diagnosed at initial metastatic presentation between January 2010 and December 2014 in a single tertiary referral centre. RESULTS We studied a total of 271 patients with a median age of 63.8 years and median follow-up duration of 5.1 mo. The majority (n = 217, 80.1%) had the peritoneum as the only site of metastasis at initial presentation. Palliative systemic chemotherapy was eventually planned for 175 (64.6%) of our patients at initial presentation, of which 171 were initiated on it. Choice of first-line regime was in accordance with the National Comprehensive Cancer Network Guidelines for Gastric Cancer Treatment. These patients underwent a median of one line of chemotherapy, completing a median of six cycles in total. Chemotherapy disruption due to unplanned hospitalizations occurred in 114 (66.7%), while cessation of chemotherapy occurred in 157 (91.8%), with 42 cessations primarily attributable to PC-related complications. Patients who had initiation of systemic chemotherapy had a significantly better median overall survival than those who did not (10.9 mo vs 1.6 mo, P < 0.001). Of patients who had initiation of systemic chemotherapy, those who experienced any disruptions to chemotherapy due to unplanned hospitalizations had a significantly worse median overall survival compared to those who did not (8.7 mo vs 14.6 mo, P < 0.001). CONCLUSION Gastric PC carries a grim prognosis with a clinical course fraught with disease-related complications which may attenuate any survival benefit which palliative systemic chemotherapy may have to offer. As such, investigational use of regional therapies is warranted and required validation in patients with isolated PC to maximize their survival outcomes in the long run.

BACKGROUND: Cholangiocarcinoma (CCA), an aggressive epithelial neoplasm of biliary tract, presents limited treatment options and poor overall survival. Aberrant fibroblast growth factor receptor (FGFR) signaling has been implicated in CCA carcinogenesis especially in intrahepatic cholangiocarcinoma (iCCA). Debio 1347 is an orally available selective FGFRi with potent antitumor effect in preclinical models of cancer bearing FGFR alterations. Debio 1347 showed encouraging preliminary clinical activity and manageable treatment-emergent adverse events (TEAE) in its first-in-human (FIH) Ph1 study (NCT1948297). Here we report results from the patients with CCA patients enrolled. METHODS: This FIH study enrolled patients with advanced solid malignancies harboring activating alterations of FGFR 1, 2, or 3. Patients received Debio 1347 at doses between 60 and 150 mg orally daily in 28-day cycles. RESULTS: Among 9 patients with CCA enrolled (as of November 20), all had iCCA, 5 patients had an FGFR2 translocation (56%), and one each had an FGFR1 translocation, FGFR2 mutation, FGFR2 activating deletion, and an FGFR3 mutation. The median number of lines of prior systemic therapy was 2 (range, 1–3). The most common TEAEs were hyperphosphatemia, nail changes, nausea, dry mouth and stomatitis. No grade ≥3 related TEAE were reported except grade 3 hyperphosphatemia (33%). Partial responses were observed in 2/9 (22%) patients, one with an FGFR2 translocation and one with an FGFR2 activating deletion; 4/9 (44%) patients had stable disease, and all had FGFR2 translocations. The median time on treatment was 24 weeks (range, 4–57 weeks). CONCLUSIONS: These results demonstrate that patients with cholangiocarcinoma with activating alterations in FGFR may benefit from treatment with Debio 1347. The phase II FUZE trial of Debio 1347 for patients with advanced solid tumors harboring FGFR fusions will include a cohort for patients with cholangiocarcinoma.

Aim The survival benefit of using a non-cross resistant second-line chemotherapy in the third-line setting in metastatic gastroesophageal cancer is unproven. We evaluated the utility of third-line chemotherapy in patients treated at a single institution. Methods Between 2010 and 2014, efficacy and toxicity data of patients who received three or more lines of systemic therapies for metastatic gastroesophageal adenocarcinoma at the National Cancer Centre Singapore was retrospectively analyzed. Results Thirty-two (6%) patients received three or more lines of chemotherapy. The median age and ECOG performance status were 59 years (36-82) and 1 (0-2), respectively. Majority of patients (88%) had tumor located in the stomach and 13 patients (41%) had diffuse histology or poorly cohesive or signet ring cells. Four (12%) patients had HER2-positive disease. Prior therapy was platinum (100%), fluoropyrimidine (97%), taxane (63%), irinotecan (28%), anthracycline (13%) and ramucirumab (3%). Third-line therapy consisted of 24 (75%) monotherapy, 6 (19%) doublet, 1 (3%) triplet chemotherapy and 1 (3%) clinical trial. Monotherapy irinotecan (44%) was most common, followed by docetaxel (19%) and paclitaxel (9%). Of 22 patients evaluable for response, there was 1 (5%) partial response, 9 (41%) stable disease. Median overall survival was 18.3 weeks (4.3-65.1). Of 30 patients evaluable for toxicities, 17 (57%) experienced at least one grade 3 or 4 toxicities. Conclusion The benefit of using non-cross resistant second-line regimens as third-line chemotherapy was small with moderate toxicity. Newer agents such as nivolumab or TAS-102 or clinical trial may be preferred.

Objective: Chemoradiation (CRT) may induce a change in systemic inflammatory state which could affect clinical outcomes in oesophageal cancer. We aimed to evaluate the changes and prognostic significance of systemic inflammatory markers following definitive CRT in oesophageal squamous cell carcinoma. Methods: A total of 53 patients treated with concurrent CRT were included in this retrospective analysis. We compared neutrophils, lymphocytes, platelets, neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) before and after CRT using Wilcoxon signed-rank test. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariable and multivariable survival analysis were performed using Cox regression analysis. Clinical univariable survival prognostic factors with p < 0.1 were included in a multivariable cox regression analysis for backward stepwise model selection. Results: Both NLR (median ∆+2.8 [IQR −0.11, 8.62], p < 001) and PLR (median ∆+227 [81.3–523.5], p < 0.001) increased significantly after CRT. Higher levels of pre-CRT, post-CRT and change (∆) in NLR and PLR were associated with inferior OS and PFS. Post-CRT NLR (HR 1.04, 95% CI 1.02–1.07, p < 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01–1.05, p = 0.005), cT-stage (HR 3.83, 95% CI 1.39–10.60, p = 0.01) and RT dose (HR 0.41, 95% CI 0.21–0.81, p = 0.01) were independent prognostic factors for OS in multivariable analysis. Change in NLR (HR 1.04, 95% CI 1.01–1.06, p = 0.001), post-CRT platelets (HR 1.03, 95% CI 1.01–1.05, p = 0.002), cT-stage (HR 3.98, 95% CI 1.55–10.25, p = 0.004) and RT dose (HR 0.41, 95% CI 0.21–0.80, p = 0.009) were independent prognostic factors for PFS. Conclusion: Both NLR and PLR increased following definitive CRT. Post-CRT NLR and ∆NLR were associated with adverse survival in oesophageal SCC. Advances in knowledge: We showed that CRT increased PLR and NLR, possibly reflecting a systemic inflammatory state which were associated with poor clinical outcomes in oesophageal SCC.

Aim To evaluate the safety and efficacy of the combination therapy of fluorouracil, leucovorin and irinotecan (FOLFIRI) and aflibercept in Asian patients with metastatic colorectal cancer (mCRC), who had progressed after oxaliplatin-based chemotherapy. Methods This is a retrospective analysis of 19 mCRC patients who received FOLFIRI and aflibercept (4 mg/kg intravenously) every 2 weeks via a Named Patient Program (supported by Sanofi Aventis) in Singapore. Treatment was administered until disease progression or unacceptable toxicities. Kaplan–Meier method was used to estimate progression-free survival (PFS) and overall survival (OS). Efficacy and toxicities were summarized using descriptive statistics. Statistical analysis was performed using STATA 12.0 software. Results The majority (84%) of the patients were of chinese ethnicity. The median age was 59 years, with 63.2% of the patients having an Eastern Cooperative Oncology Group status of 1. Four patients (21.1%) achieved partial response and 8 patients (42.1%) achieved stable disease. After a median follow-up of 9.6 months [95% confidence interval (CI), 2.2–13.1 months], the median OS was 11.6 months (95% CI, 6.1 to not-estimable), and median PFS was 4.1 months (95% CI, 2.2–5.9). Majority of the toxicities were grade 1–2, and include leucopenia (84.2%), anemia (73.7%), liver enzyme elevation (68.4%) and fatigue (68.4%). The most frequently reported grade 3 toxicities were neutropenia and neutropenic complications (both 15.8%). All adverse events resolved with supportive management. Conclusion The clinical benefit and safety profile of the combination of FOLFIRI/aflibercept in Asian patients with mCRC are consistent with that of Western population. FOLFIRI/aflibercept may be an appropriate therapeutic option in Asian patients with mCRC previously treated with an oxaliplatin-based regimen.

3603 Background: Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Here we report the results of the expansion portion of a Phase 1 study of advanced solid tumors patients (pts) harboring an FGFR1-3 gene fusion. Methods: Pts with advanced refractory solid tumors harboring an FGFR1-3 gene fusion were enrolled. Based on results from the dose escalation portion, pts received Debio1347 80 mg once daily (qd) in 28-day cycles. Pharmacokinetics (PK) and pharmacodynamics were evaluated. The data cut-off was October 8, 2019. Results: Among 18 pts enrolled, 5 had primary brain tumors (PBT), 5 had cholangiocarcinoma, 2 had urothelial cancer, 2 had colon cancer, 1 patient each lung neoplasm, gastric cancer, endometrial cancer and squamous cell carcinoma of the chest wall. Tumors harbored fusions with FGFR1 (n = 1), FGFR2 (n = 8), and FGFR3 (n = 9). All had prior systemic therapy (median 3 lines; range 1-4). The most common treatment emergent adverse events were fatigue (50%), hyperphosphatemia (44.4%), anemia (38.9%), alopecia (33.3%), nausea (33.3%), vomiting (33.3%), constipation (33.3%), and palmar-plantar erythrodysesthesia syndrome (22.2%). Blurred vision was reported in 1 pt. There were no findings on ocular exams compatible with retinal detachment. No grade 3 AE related to study drug were reported. One patient needed dose reduction due to grade 2 nails toxicity. In PK analysis, plasma steady-state was rapidly achieved and serum phosphate increase correlated with Debio 1347 plasma exposure, confirming target engagement at 80 mg qd. Median follow-up was 18 weeks. Partial responses were observed in 3 pts harboring an FGFR2 fusion: 1 out of 2 colon cancer and 2 out 5 cholangiocarcinoma. Median duration of response was 16.1 weeks (range: 8.4-22.8+). Overall disease control was observed in 11 out of 14 pts without PBT (79%). Median PFS was 18.3 weeks. No signs of activity were observed in the 5 patients with PBT, all with an FGFR3-TACC3 fusion. Conclusions: Debio 1347 at the recommended dose of 80 mg qd was generally well tolerated and showed signs of activity in solid tumors harboring an FGFR fusion. The FUZE phase 2 clinical trial of Debio 1347 is recruiting FGFR fusion-positive advanced solid tumors irrespectively of tumor histology, excluding PBT. Clinical trial information: NCT01948297 .

4590 Background: Nivolumab (N) and Y90-radioembolization (RE) are both therapeutic options in advanced hepatocellular carcinoma (aHCC). Increasing evidence suggests that radiotherapy synergizes with immune checkpoint inhibitors to augment anti-tumour effects. Methods: Eligible Child-Pugh A aHCC patients (pts) were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies together with circulating biomarkers were obtained. Primary end-point was overall response rate (ORR) (per RECIST v 1.1). Overall response was defined as the composite overall response observed for the lesions within Y90-RE field and outside Y90-RE field. Key secondary end points included disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. 36 evaluable pts were needed to assess whether the addition of N improved the ORR of Y90-RE from 21% to 41% as determined by Simon two-stage optimal design with 80% power and one sided significance level of 0.05. Results: Forty pts were enrolled of which 36 were evaluable. At baseline: 63.9% were HepB in aetiology; 63.9% BCLC stage C; 47.2% had AFP > 400ng/mL; number of liver lesions – median 5 (range 1- 20); size of largest liver lesion – median 80mm (range 14-177mm); 27.8% had prior TACE; and 13.9% had prior systemic therapy. ORR was 31% (95% CI 16.4 - 48.1%). Eight out of 11 responders had not progressed at study cut-off. DCR was 58.3%. 81% of target lesions within Y90-RE field regressed. With a median follow up of 16.4 months, median PFS and OS were 4.6 months (95% CI 2.3m - 8.4m) and 15.1 months (95% CI 7.8m - NE) respectively. Six- and 12-month PFS rates were 44.2% (95% CI 27.3% - 59.9%) and 26.1% (95% CI 11.2% - 43.8%) respectively. Overall, N+ Y90-RE was well tolerated and safe; only 11% had grade 3/4 treatment related adverse events (AEs). Responders demonstrated significant alterations of LIF, MIG and Eotaxin3 levels in the pre-treatment cytokine analyses. Conclusions: Combination N+Y90-RE resulted in an encouraging ORR of 31% (95% CI 16.4 - 48.1%) in aHCC. 81% of target lesions within Y90-RE field regressed suggesting synergy in combining Y90-RE with nivolumab. This combination is safe and tolerable with low G3/4 treatment related AEs of 11%. Further biomarker analyses will be presented at the meeting. Clinical trial information: NCT03033446 .

730 Background: Tumoral KRAS mutations (KRAS mt) are detected in ~80% of APC and associated with a negative prognosis. Digital droplet PCR (ddPCR) has high sensitivity for circulating KRASmtbut narrower gene coverage. NGS using hybrid-capture methods has reported ctDNA KRASmtin ~30% of patients (pt). We previously presented clinical results of the Phase I trial of OXIRI (GI ASCO 18 #411). We now present the first prospective evaluation of ctDNA in APC by an amplicon-based NGS approach in this Phase I trial. Methods: Paired ctDNA and CA19-9 samples were taken at baseline, C2D1, C3D1 and end of trial. A targeted panel with error-correction (Lucence Diagnostics) was used to detect for mtin KRAS, TP53, SMAD4, CDKN2A, CTNNB1, GNAS, APC and MYC. CT scans were performed every 2 cycles. Survival curves by Kaplan Meier were compared by mutational status, ctDNA and CA19-9 response using the log-rank test. Spearman correlation of ctDNA and CA19-9 changes was performed. Results: ctDNA mtwas detected at baseline in 19/23 (83%) samples, comprising KRAS 17/23 (73%), TP53 (61%), SMAD4 (48%) and CDKN2A (30%). KRAS mtand SMAD4 mt conferred a negative prognosis for overall survival with a hazard ratio of 4.2 (CI: 1.6-10.4; p = 0.01) and 2.8 (CI: 0.9-8.65; p = 0.01) respectively. Drop in ctDNA and CA19-9 was associated with a trend for longer progression free survival at C2D1 (both) and C3D1 (ctDNA only). Radiological partial response (PR) was associated with lower ctDNA in 5/5 pt and CA 19-9 in 4/5 pt. Decrease in ctDNA and CA19-9 was associated with disease control (PR/SD) at C2D1 in 11/14 pt and 10/10 pt; at C3D1 in 11/12 pt and 6/7 respectively. No significant correlation between the amplitude of CA19-9 and ctDNA changes was found. Conclusions: ctDNA could be detected in 83% of pts of whom KRAS mtrates were similar to reports using tissue NGS. Determination of RAS mtand SMAD4 mtin ctDNA may aid in the prognostication of pts and decrease in ctDNA levels may predict for treatment benefit, similar in extent to CA 19-9. This may be particularly useful in non-CA19-9 secreting APC as an adjunct to imaging. Clinical trial information: NCT02368860.

Tumor-specific antibody drugs can serve as cancer therapy with minimal side effects. A humanized antibody, PRL3-zumab, specifically binds to an intracellular oncogenic phosphatase PRL3, which is frequently expressed in several cancers. Here we show that PRL3-zumab specifically inhibits PRL3+ cancer cells in vivo, but not in vitro. PRL3 antigens are detected on the cell surface and outer exosomal membranes, implying an ‘inside-out’ externalization of PRL3. PRL3-zumab binds to surface PRL3 in a manner consistent with that in classical antibody-dependent cell-mediated cytotoxicity or antibody-dependent cellular phagocytosis tumor elimination pathways, as PRL3-zumab requires an intact Fc region and host FcγII/III receptor engagement to recruit B cells, NK cells and macrophages to PRL3+ tumor microenvironments. PRL3 is overexpressed in 80.6% of 151 fresh-frozen tumor samples across 11 common cancers examined, but not in patient-matched normal tissues, thereby implicating PRL3 as a tumor-associated antigen. Targeting externalized PRL3 antigens with PRL3-zumab may represent a feasible approach for anti-tumor immunotherapy., Phosphatase of regenerating liver 3 (PRL3) is usually found intracellularly, and is over-expressed in cancer cells. Here the authors show that PRL-3 is also detectable on cell surface, and can be recognized by PRL3-zumab to recruit immune cells into tumor to promote anti-tumor immunity, thereby implicating PRL-3 as a potential tumor antigen.

Circulating tumour DNA (ctDNA) has the potential to be a specific biomarker for the monitoring of tumours in patients with colorectal cancer (CRC). Here, our aim was to develop a personalised surveillance strategy to monitor the clinical course of CRC after surgery. We developed patient-specific ctDNA assays based on multiplexed detection of somatic mutations identified from patient primary tumours, and applied them to detect ctDNA in 44 CRC patients, analysing a total of 260 plasma samples. We found that ctDNA detection correlated with clinical events – it is detectable in pre-operative but not post-operative plasma, and also in patients with recurrent CRC. We also detected ctDNA in 11 out of 15 cases at or before clinical or radiological recurrence of CRC, indicating the potential of our assay for early detection of metastasis. We further present data from a patient with multiple primary cancers to demonstrate the specificity of our assays to distinguish between CRC recurrence and a second primary cancer. Our approach can complement current methods for surveillance of CRC by adding an individualised biological component, allowing us not only to point to the presence of residual or recurrent disease, but also attribute it to the original cancer.

BACKGROUND: Varlitinib is a nanomolar inhibitor of EGFR, HER2, and HER4 and has shown potent anti-tumor activity as monotherapy in preclinical BTC models. During phase (Ph) 1 development, significant tumor shrinkage was observed in biliary tract cancer (BTC) patients (pts). Tissue microarray analysis has revealed that ~70% of BTC pts exhibit HER overexpression, suggesting varlitinib could be beneficial in BTC. METHODS: Data from BTC pts were pooled from 3 Ph1 trials of varlitinib (dosed 200–500 mg BID) in combination with cisplatin and 5-FU/capecitabine (cape) (study 002); oxaliplatin and 5-FU/cape (study 002SG); cisplatin and gemcitabine (study 007). The depth of tumor response, disease control rate (DCR), and treatment-related adverse events (TRAEs) were analysed. RESULTS: As of 12 June 2018, 43 pts were recruited: 12 (27.9%); 10 (23.3%) and 21 (48.8%) from study 002; 002SG and 007 respectively. Studies 002SG and 007 were still ongoing at data cut-off. Twenty (46.5%) pts were male and the median age was 62 years (range, 42–82 years). Most tumors were cholangiocarcinoma (74.4%), followed by gallbladder cancer (16.3%) and carcinoma of the ampulla of Vater (9.3%). Fourteen (32.6%) pts had received ≥1 prior lines of treatment. Of the 37 pts evaluable for efficacy (those with measurable disease and received ≥1 dose of treatment), partial responses were observed in 10 (27.0%) pts and stable disease in 16 (43.2%) pts, with a DCR of 70.3%. The median depth of tumor response was −10.8% (range, −87.1% to 49.5%). Of 43 pts, the most frequent (≥30%) TRAE (any grade) were fatigue (37%), decreased appetite (34%), and nausea (32%) and the most common grade ≥3 TRAE were hyperbilirubinemia (12%), increased AST (9%), and neutropenia (9%). The median PFS data is not matured and will be provided if evaluable at the time of presentation. CONCLUSIONS: Varlitinib with platinum-based chemotherapy has a promising efficacy and safety profile in BTC. A Ph2/3 randomised study of varlitinib and cape in 2nd line BTC and a Ph1b/2 study of varlitinib with platinum-based chemotherapy in 1st line BTC are ongoing.

331 Background: Varlitinib is a nanomolar inhibitor of EGFR, HER2, and HER4 and has shown potent anti-tumor activity as monotherapy in preclinical BTC models. During Phase (Ph) 1 development, significant tumor shrinkage was observed in biliary tract cancer (BTC) patients (pts). Tissue microarray analysis has revealed that ~70% of BTC pts exhibit HER overexpression, suggesting varlitinib could be beneficial in BTC. Methods: Data from BTC pts were pooled from 3 Ph1 trials of varlitinib (dosed 200-500 mg BID) in combination with cisplatin and 5-FU/capecitabine (cape) (Study 002); oxaliplatin and 5-FU/cape (Study 002SG); cisplatin and gemcitabine (Study 007). The depth of tumor response, disease control rate (DCR), and treatment-related adverse events (TRAEs) were analysed. Results: As of 12 June 2018, 43 pts were recruited: 12 (27.9%); 10 (23.3%) and 21 (48.8%) from study 002; 002SG and 007 respectively. 002SG and 007 were still ongoing at data cut-off. 20 (46.5%) pts were male and the median age was 62 years (range 42-82). Most tumors were cholangiocarcinoma (74.4%), followed by gallbladder cancer (16.3%) and carcinoma of the Ampulla of Vater (9.3%). 14 (32.6%) pts had received ≥ 1 prior lines of treatment. Of the 37 pts evaluable for efficacy (those with measurable disease and received ≥ 1 dose of treatment), partial responses were observed in 10 (27.0%) pts and stable disease in 16 (43.2%) pts, with a DCR of 70.3%. The median depth of tumor response was -10.8% (range 49.5% to -87.1%). Of 43 pts, the most frequent (≥ 30%) TRAE (any grade) were fatigue (37%), decreased appetite (34%), and nausea (32%) and the most common Grade ≥ 3 TRAE were hyperbilirubinemia (12%), increased AST (9%), and neutropenia (9%). The median PFS data is not matured and will be provided if evaluable at the time of presentation. Conclusions: Varlitinib with platinum-based chemotherapy has a promising efficacy and safety profile in BTC. A Ph2/3 randomised study of varlitinib and cape in 2nd line BTC and a Ph1b/2 study of varlitinib with platinum-based chemotherapy in 1st line BTC are ongoing. Clinical trial information: NCT02648425, NCT02435927, and NCT02992340.

65 Background: Trastuzumab (T) + chemo is standard first-line therapy (tx) for HER2+ gastroesophageal adenocarcinoma (GEA) pts, though progression ensues in 6-8 months. The approved second-line tx is ramucirumab +/- paclitaxel (R+PAC). Pts with GC are less responsive to R+PAC than gastroesophageal junction (GEJ) pts, in particular HER2+ GC, and no anti-HER2 agents are approved in post-T setting. We report results of combination M+P in HER2+ GC pts and describe a biological rationale for this population. M is an anti-HER2 mAb Fc optimized for enhanced binding to activating FcgRIIIa (CD16A) and decreased binding to inhibitory FcgRIIb (CD32B). M demonstrated an enhanced Fc-dependent MoA, including enhanced ADCC. Methods: HER2+, PD-L1-unselected, second-line GEA pts post T progression received M (15 mg/kg) + P (200 mg) Q3wk. Safety, objective response rate (ORR), median overall & progression-free survival (mOS, mPFS), disease control rate (DCR), circulating tumor DNA, & tumor PD-L1 expression were assessed. Results: To date, 66 GEA pts were dosed; 35 (53%) GC and 31 (47%) GEJ. Overall, 12/66 (18.2%) had tx-related adverse events ≥ grade 3; 5 had drug-related SAEs: dehydration, diabetic ketoacidosis, hypotension and pneumonitis, each a single event, and 2 events of autoimmune hepatitis. Eligibility was based on archival HER2 expression; an exploratory endpoint measured retention of HER2 expression post-T by ERBB2 ctDNA. HER2 expression was lost in 23/56 (41.1%) of pts tested post T. HER2 retention was higher in pts with GC versus GEJ (65.8% vs. 44.8%) and in GEA pts with IHC 3+ vs 2+ archival tumors (61.7% vs 47.4%, respectively). Furthermore, GC had higher PD-L1 expression than GEJ, 53.3 vs. 33.3%, respectively. This coincided with more responses in IHC3+ GC pts, ORR 12/29 (41.4%; 95% CI 23.5-61.1), DCR 21/29 (72.4%; 95% CI 52.8-87.3), mPFS 5.5 months (95% CI 2.3-7.6), mOS not reached, with lower bound of 9.1 months for 95% CI. Enrollment of an additional 25 pts enriched for IHC3+ GC is ongoing. Conclusions: Results suggest that M+P, a chemo-free regimen, demonstrates acceptable tolerability and has encouraging preliminary activity in second-line HER2+ GEA, specifically in GC pts who retain ERBB2 amp prior to second-line tx. Clinical trial information: NCT02689284.

29 Background: The incidence rates of gastric cancer in Asia are among the highest in the world. Gastric cancer is a heterogeneous disease. The Cancer Genome Atlas and Asian Cancer Research Group provide molecular classification of gastric cancers. Recently, immunotherapy was found to be effective in selected gastric cancer patients. Despite the molecular classification, a classification system based on immune microenvironment is in need to better stratify patients for ideal immunotherapy combinations. Methods: We have performed indexed-sorting single cell RNA-seq to analyze both CD45+ and CD45- cells from biopsy samples of 15 gastric cancer patients (5 Diffuse; 4 Intestinal; 5 Mixed; 1 unknown type). Using our ezsinglecell analytical pipeline, we have built a draft Asian Single-cell Immune Atlas (ASIA) of human gastric cancers. Results: We were able to probe fibroblast, epithelial cells and various subtypes of immune cells. Interestingly, we observed that fibroblast and mast cells were more enriched in diffuse type. In addition, we have profiled single immune cells in tumor and normal adjacent tissues to distinguish tissue-induced versus tumor-driven immune signatures. Comparing tumor and normal tissues, we found that tumor site has less natural killer (NK) and CD8 T cells; more B, myeloid and CD4 T cells. Moreover, CD8 T cells and NK cells showed distinct phenotypes in tumor compared to normal tissues. In particular, inhibitory receptor Tim-3 and CTLA-4 were up-regulated in the tumor. Most interestingly, T Cell Receptor (TCR) reconstruction revealed clonal expansion of CD8 T cells. Conclusions: Both immune (CD45+) and non-immune (CD45-) cell components of human gastric cancers are highly heterogeneous. Diffuse type showed differential tumor microenvironment compared to intestinal and mixed types. Tumor site presented an immune-suppressive phenotype compared to normal adjacent site. The clonal expansion of CD8 T cells suggested the role of adaptive immunity on recognizing tumor antigens. This discovery may determine the clinical applications of immunotherapy for gastric cancer in the future.

3612Background: Brain metastases (BM) from colorectal cancer (CRC) are a rare but increasing event as patients survive longer. While human epidermal growth factor receptor 2 (HER2) gene amplificati...

4030Background: T + chemo is standard 1st line therapy (tx) for HER2+ GEA patients (pts). However, pts typically progress within 6-8 months, with up to 30% demonstrating loss of HER2 positivity. No...

411 Background: The FOLFIRINOX regimen is highly active in APC, but its use is limited by toxicity. Irinotecan (IR) toxicity is correlated with UGT1A1 genotype status and chronomodulated delivery of fluoropyrimidines may reduce toxicity and increase efficacy. We have presented the dose escalation (DES) of OXIRI. In dose expansion (DXP), several pts required dose reduction after cycle 1 and we evaluated a lower starting dose. We now present data of the recommended Phase II dose (RP2D) and DES combined. Methods: Pts with APC and ECOG performance status ≤2, adequate organ function were enrolled. Previous OX or IR exposure was disallowed. During DES, APC pts homozygous for UGT1A1*6/*6 or UGT1A1*28/*28 were excluded. During DXP, only pts progressing on ≥ 1 line prior chemo was allowed and IR was dosed according to UGT1A1 genotype. At RP2D, pts received iv OX 37.5mg/m2 and IR 50mg/m2 on D1, 8 and po capecitabine 2650mg once at midnight on D1-14 every 21D until progression. Results: A total of 25 pts were enrolled, 17 in DES and 8 in DXP, 21 had metastatic and 4 had locally advanced APC. Male:Female 11:14, median (range) age and ECOG PS was 65yrs (50-77) and 0 (0-1) respectively. Pts with 0, 1 or 2 lines of prior chemo were 4 (16%) , 14 (56%) and 7(28%) respectively. Grade 3/4 AEs (≥5%) related to OXIRI were neutropenia (32%), anaemia (12%), diarrhoea (16%). No events of febrile neutropenia were reported. At data cut-off on 31 Aug 2017, 4 pts are on study. Median progression-free and overall survival was 22 and 35 wks respectively. Response rate (RR) was 5/25 (20%, overall); 5/20 (25%, evaluable pts) including 1 complete response and 1 unconfirmed partial response. Disease control rate for ≥ 12wks was 16/25 (64%) with 3 pts > 52wks. CA19-9 decrease of ≥ 20% was seen in 9/25 pts. Conclusions: OXIRI is an active regimen with RR of 20% despite 84% of pts having prior chemo, with disease control for ≥ 12wks in 64% of pts. Predominant toxicity was neutropenia. This study was supported by the National Medical Research Council Singapore. Clinical trial information: NCT02368860.

TPS542 Background: In recent years, Yttrium-90 (Y90) trans-arterial radioembolization (TARE) has emerged as a therapeutic option for intermediate stage hepatocellular carcinoma (HCC). Cancer immunotherapy targeting tumour immune evasion has shown remarkable successes in various cancers. Nivolumab, an immune checkpoint inhibitor of programmed death 1 (PD1), has demonstrated encouraging activity in advanced stage HCC. Similarly, chronic hepatitis B virus (HBV) infection, a strong risk factor for HCC, is characterized by immune escape mechanisms. We hypothesize that TARE will stimulate tumor and/or HBV specific T cell responses that can be boosted using nivolumab. We thus propose an open label phase 2 trial investigating the combination of TARE with nivolumab in BCLC intermediate stage HCC. Methods: Eligible patients (pts) have ECOG performance status ≤ 2, Child-Pugh A score, intermediate stage HCC planned for TARE according to institutional practice with adequate organ function. Pts will be treated with TARE followed by nivolumab 240mg, 21 days after TARE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies will be taken. Primary end-point is response rate (RR) of combinational TARE and nivolumab. Key secondary end points are: progression free survival, overall survival, safety and quality of life using FACT-HEP score and EORTC QLQ-C30. Exploratory objectives are to evaluate how tumor PD L-1 expression, HCC mutational burden and blood lymphocyte activation/phenotypic profiles correlate with tumor response. Where possible, serial changes in antigen-specific T cell responses to HBV and/or tumour antigens will also be assessed. This study aims to enroll 40 pts as calculated using the Simon two-stage optimal design with 80% power and one sided significance level of 0.05. This will assess whether the addition of nivolumab improves the RR of TARE at 8 weeks from 21% to 41%. Patient accrual was initiated in December 2016 and as of September 2017, 9 pts have been treated. Clinical trial information: 03033446.

140 Background: Trastuzumab (T) + chemotherapy (ctx) is standard for 1st line advanced HER2+ GEA, yet subsequent targeted options are lacking. M is an anti-Her 2 monoclonal antibody with an optimized Fc domain to increase affinity for activating CD16A Fc-receptors (FcR) on NK cells. Outcomes for T-treated patients (pts) carrying the low-affinity CD16A-F allele are generally worse than pts homozygous for the high-affinity V allele. M is designed to be FcR genotype independent. Evidence of clinical activity of M alone has been seen in HER2+ GEA pts post T, while P has demonstrated durable activity. Loss of HER2 amplification may occur after T failure in a subset of initially HER2+ GEA pts. Preclinical studies suggest that engagement of innate and adaptive immunity with the combination of anti-HER-2 antibodies and T-cell checkpoint inhibition could achieve greater antitumor activity than either agent alone. Methods: Advanced HER2+, PD-L1-unselected GEA pts post T failure were eligible. Dose escalation evaluated 10 and 15 mg/kg M and 200 mg P for 2nd line or higher pts. Cohort expansion evaluates safety and objective response rate (ORR) by RECIST v1.1 in 2nd line pts. M + P is given every 21 days; response assessed every 6 weeks. HER2 amplification status was assessed in a subset of pts by plasma circulating tumor (ct) DNA analysis prior to Cycle 1 of M+P. Results: Dose escalation enrolled 9 pts; cohort expansion 48 pts at 15 mg/kg M: 30 in North America (NA) and 18 in Asia (A). Treatment was well tolerated, with 1 drug-related serious adverse event. Of 38 evaluable pts to date in expansion (24 NA and 14 A), the best overall responses include 7 pts (18.4%) with PR (4 confirmed and 3 unconfirmed) and 11 (28.9%) with SD. Higher ORR trends were observed in A vs NA (35.7% vs 8.3%) and G vs GEJ (31.6% vs 5.3%). Of 25 pts with ctDNA results, HER2 amplification detection was higher in GC than GEJ (80% vs 53%). Responses were independent of FcR genotype; CD16A genotype for evaluable pts with PR: 1 V/V, 2 V/F, 2 F/F with similar allelic distribution among non-responders. Conclusions: M+P is a well-tolerated ctx-free regimen that has shown preliminary antitumor activity in 2nd line pts with advanced/metastatic GEA. Clinical trial information: NCT02689284.

The use of trastuzumab, a monoclonal antibody targeting the HER2 protein, in combination with 5-fluorouracil/platinum-based chemotherapy improves survival in patients with HER2-positive advanced gastric cancer. In addition, TS-one (S-1)/platinum is also used as a standard of care in Asian countries. However, little is known about the combination of S-1/cisplatin chemotherapy and trastuzumab in patients with HER2-positive advanced gastric/gastroesophageal junction (GEJ) cancer. We conducted a single-arm, two-stage, open-label, multicenter phase II study. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 mg/kg and 6 mg/kg on day 1 of subsequent cycles. Cisplatin was administered intravenously at 60 mg/m2 on day 1 of each cycle after trastuzumab. S-1 was administered orally [based on body surface area (BSA)] twice a day for 14 days in a 3-weekly cycle. Patients with BSA of

There is currently no standard salvage chemotherapy regimen in relapsed and refractory lymphoma. Gemcitabine is a novel nucleoside analogue, which acts synergistically with cisplatin both in vitro and in clinical studies. We evaluated the combination of gemcitabine, cisplatin and methylprednisolone (GEM-P) in 41 heavily pretreated patients with relapsed and refractory Hodgkin's and non-Hodgkin's lymphoma. The best-achieved response rate (RR) was 79% (95% CI 64–91), with a complete RR of 21%. In patients with chemo-resistant disease, the RR was 63%. Myelosuppression was the main toxicity, the incidence of Grade 3 or 4 anaemia, neutropenia and thrombocytopenia was 17.1, 61.0 and 53.7% respectively. Only one patient had neutropenic sepsis and none of the patients suffered from haemorrhage. Grade 3 or 4 nonhaematological toxicity was minimal and stem cell mobilisation was not inhibited. GEM-P is an effective salvage regimen and its use prior to autologous stem cell transplant warrants further investigation.

2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, an enzyme required for palmitoylation and secretion of all Wnt ligands. In preclinical studies, ETC-159 induced tumour regression in patient-derived xenograft models. Methods: Open-label, multi-centre study to determine safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics (PD) of ETC-159 given orally, once every other day in a 28d cycle. PD was evaluated by AXIN2 mRNA levels in whole blood and hair follicles and bone turnover by radiological and serum markers. Dose escalation was by ordinal continual reassessment method with a dose-limiting toxicity (DLT) period of 28d. Results: As of 18 Jan 2017, 16 patients (pts) were treated in 6 cohorts at 1 mg (2pts), 2 mg (2pts), 4 mg (3pts), 8 mg (4pts); 16 mg (3pts), and 30 mg (2pts). 80% were male, median age (range) was 55yr (19-68). One DLT was seen at 16 mg due to hyperbilirubinaemia. Adverse events (≥ 20%) were vomiting (32%); anorexia and fatigue (31%); dysgeusia and constipation (25%). ETC-159 Cmax increased with dose with a mean t1/2 of 14 hr. Plasma levels of ETC-159 that inhibited colony formation in vitro were attained from 4 mg onwards. Reduction of whole blood and hair follicle AXIN2 mRNA levels and doubling of serum β-CTX levels was first observed at 4 mg and at C1D15 in some patients. PD modulation increased with dose, consistent with on-target modulation of Wnt signalling. Two pts had β-CTX rise > 1000 pg/mL (reference limit) and a ≥ 5% reduction in bone density by C3D1. Both took vitamin D and calcium supplements and were given i.v. bisphosphonates. No responses were seen but 2 pts (2 mg: colorectal and 4 mg: peritoneal carcinoma) had stable disease for 6 and 8 cycles respectively. Dose-escalation is ongoing at 30 mg. Conclusions: ETC-159 inhibits Wnt signalling at doses that are well tolerated. β-CTX levels increased early on, and in two pts were associated with reduced bone mineral density. Early and regular monitoring of bone turnover is indicated. This study was sponsored by D3 which is funded by NMRC, NRF and BMRC Singapore. Clinical trial information: NCT02521844.

48 Background: Theoxaliplatin/S-1 (SOX) and cisplatin/S-1 (SP) regimens are interchangeably used in the management of advanced gastric cancer (AGC). We previously developed a classification tool using gene expression signatures which successfully stratified gastric cancer cell lines and primary tumour samples according to their sensitivity to SOX or SP ( Tan et al, Gastroenterology 2011). We now report the first prospective study to evaluate the feasibility and efficacy of using a genomic classifier to tailor treatment in this setting. Methods: Pts with histologically-confirmed locally-advanced, metastatic and recurrent GC were recruited from 3 centres in Singapore and South Korea. Tumours were analysed using the Affymetrix HG-U133 Plus 2.0 array and results were used to classify pts as G1 (oxaliplatin-sensitive), G2 (cisplatin-sensitive) and G3 (status unclear or gene expression not available). G1 and G2 pts were matched to SOX and SP regimens respectively, while G3 pts were assigned SOX. The primary endpoint was best overall response; secondary endpoints were turnaround time and biomarker analyses. Results: Between July 2, 2010, and Apr 2, 2015, we screened 85 AGC pts. 74 pts received at least 1 cycle of treatment and were evaluable for analysis. Median turnaround time was 7 working days (IQR, 5–9). The misclassification rate was 6%. After an initial 30 pts in the G1 subgroup were treated with SOX, subsequent pts ( N = 13) classified as G1 received the SP regimen. The ORR were 44.8%, 8.3%, 26.7% and 55.6% for G1 SOX, G1 SP, G2 SP ( N = 19), G3 SOX ( N = 12) respectively; and was higher in G1 pts treated with SOX compared with SP ( P = 0.033). Post hoc genomic reclassification based on Lei et al (Gastroenterology 2013) confirmed the utility of the metabolic subtype as a predictive marker of benefit from chemotherapy (log rank P value for PFS = 0.004). Conclusions: This bench-to-bedside effort establishes that molecular profiling to direct choice of conventional chemotherapy for AGC is possible within a reasonable timeframe. The clinical utility of our genomic classifiers in question are promising but warrant further investigation. Clinical trial information: NCT01100801.

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity first described in 1996 by Hinchey et al, most commonly associated with hypertensive encephalopathy, eclampsia in pregnant women, immunosuppressants and cytotoxic agents. In recent years, anti-angiogenic agents as a novel class of anti-cancer therapies have become a standard of care for certain tumours. Correspondingly, there have been an emerging number of case reports documenting PRES associated with these anti-angiogenic therapies. As the manifestations of PRES are often non-specific, but could rarely lead to permanent neurological disability or even death, it is crucial that physicians are aware of PRES in relation to anti-angiogenic therapy to promptly institute appropriate management to achieve the best outcomes for patients.

2500Background: Phosphatidylinositol-3-kinase (PI3K) and fibroblast growth factor receptor (FGFR) pathway dysregulation can co-occur in tumors. In this study (NCT01928459), safety, tolerability, and preliminary activity of the pan-FGFR (BGJ398) + α-specific PI3K (BYL719) inhibitors were evaluated and maximum tolerated dose (MTD) was established in pts w/ advanced solid tumors w/ PI3K catalytic subunit (PIK3CA) mutations ± FGFR alterations. Methods: Pts w/ solid tumors received once-daily (QD) BGJ on D1-D21 of each 28-D cycle (C) and BYL continuously during escalation (PIK3CA-mutant ± FGFR-altered) and expansion (arm 1, PIK3CA-mutant [n = 15]; arm 2, PIK3CA-mutant + FGFR-altered [n = 10]; arm 3, PIK3CA-mutant + FGFR-altered breast cancer [n = 10]). Results: Of 62 pts enrolled, 44% had ≥ 4 prior therapies. The MTD, 125 BGJ + 300 BYL, was determined based on 32 evaluable pts’ data during escalation. C1 dose-limiting toxicities (DLTs) occurred in 4 pts (table). During expansion, 24 pts in arms 1 (n = 12), 2 (...

Background: Recombinant compound interferon (rSIFN-co) is a new class of interferon derived from altering the spatial structure and configuration of the basic interferon protein. rSIFN-co displayed greater anti-tumor activity in solid tumors compared to interferon α-2b in pre-clinical studies. Methods: Patients with advanced malignancies were enrolled to determine the safety, tolerability, recommended phase II dose (RP2D), pharmacodynamics (PD) and preliminary anti-tumor activities in a 3+3 dose escalation design. Two pre-defined dose levels were planned. rSIFN-co was dosed 3 times a week via subcutaneous injection for 21 days followed by 7 days rest. This was preceded by a lead in phase. PD studies comprised of FDG-PET, pre- and post treatment changes in plasma cytokine profile and tumor repressive/ enhancing genes as well as 2'5'-oligoadenylate synthetase levels. Results: Results presented are based on preliminary data collected as of Jan. 27, 2015. 22 patients (median age 65.5 years, 14 male and 8 female) have been enrolled with 21 evaluable for safety and 15 amenable to efficacy analysis. 10 hepatocellular carcinoma (HCC), 6 non-small cell lung cancer (NSCLC), 4 colorectal cancer (CRC), 1 melanoma and 1 nasopharyngeal carcinoma patients (pts) were dosed at 2 dose levels. The RP2D was 24μg 3x/week for 21days followed by 7 days rest. No dose limiting toxicities were encountered. Most adverse events (92%) were CTCAE grade 1 and 2. The most frequent grade 1/2 treatment related adverse events (trAEs) were flu-like symptoms (90%), anorexia (33%), fatigue (33%), weight loss (33%), nausea (29%), thrombocytopenia (29%), and diarrhea (24%). Grade 3/4 trAEs were fever (2 pts), leucopenia (2 pts), transaminitis (2 pts), weight loss (1 pt), fatigue (1 pt), afebrile neutropenia (1 pt) and syncope (1 pt). 11 patients had stable disease (SD) and 4 patients had progressive disease (PD). 4 patients (2 HCC, 1 NSCLC and 1 CRC) had prolonged stable disease (>16 weeks). Detailed PD data will be presented for all cohorts. Conclusion: The RP2D was 24μg three times a week for 21days followed by 7 days rest with a lead in phase. Modest activity was seen in heavily pre-treated advanced solid tumor patients. Citation Format: Su Pin Choo, Wai Meng Tai, Maria Macapagal, Aziah Ahmad, Greg Li, Mui Leng Goh, Matthew Ng, Tira Tan, Shao Weng Tan, Wan Teck Lim. A phase I open-label, non-randomized study of recombinant compound interferon (rSIFN-co) in patients with advanced solid tumors. [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 A027.

We examined the cardiotoxicity in 153 patients treated with capecitabine and oxaliplatin in two prospective trials for advanced colorectal cancer. Ten patients (6.5%) developed cardiac events. One patient (0.7%) had sudden death, one patient developed cardiac failure with raised troponin I while another developed ventricular tachycardia (VT). The remaining seven patients (4.6%) experienced angina and three of the seven patients had raised troponin I, one of which developed ventricular fibrillation. Eight events occurred within cycle 1 (median cycle 1 day 10). Four patients with angina and one patient with VT recovered on stopping capecitabine, four patients required additional medical management and the remaining patient died suddenly at home. Patients with ischaemic heart disease appeared to be at increased risk. Physicians and patients need to be aware of these complications, so that prompt discontinuation of treatment and appropriate interventions may be instituted.

Background. Colorectal cancer (CRC) is the 3rd most common cancer globally. In cancer, the 2 most critical events that adversely affect outcomes are the emergence of metastasis and drug resistance. Blood-based markers permit the non-invasive serial monitoring of patients in order to study and track the emergence and evolution of metastasis and drug resistance. The multiple varied platforms utilize different components of blood (buffy coat, whole blood, plasma). We seek to establish a longitudinal observational study to simultaneously evaluate multiple blood-based biomarkers to track patient outcomes in colorectal cancer. Methods. In a planned 800 patient study, we prospectively recruit patients with all stages of CRC, focusing on patients with stage 3/4 CRC. At each patient's venipuncture performed during his/her routine clinical care, we serially collect additional blood specimens. All major components of the collected blood (buffy coat, red cells, whole blood and plasma) are stored. In patients undergoing primary tumor resection or metastasectomy, frozen tissue specimens are also prospectively collected and banked for subsequent biomarker analysis. A prospective electronic database of clinical information and patient outcomes is simultaneously maintained for the purpose of correlation with molecular assays. Results. To date, we have recruited 450 patients and obtained their serial blood samples. Blood is prospectively collected in an optimized manner to support the pre-analytical requirements of the different platforms. This includes whole blood for immediate assay performance (circulating tumor cells), buffy coat for immediate analysis or storage for pooled analysis (cell based assays, germline polymorphisms, white cell gene expression and assays on peripheral blood mononuclear cells), plasma for storage for pooled analysis (circulating cell free nucleic acids including DNA, miRNA, RNA and methylated DNA, novel proteomic tumor markers, cytokines). Optimization of pre-analytical processing, transport and storage parameters was carried out to enable studies across multiple platforms in this same cohort of patients to be performed in a prospective longitudinal manner. Conclusions. In this ongoing study, we have established a system for the simultaneous evaluation of multiple blood-based biomarkers operating on the various components of blood. Together with paired tissue specimens and a prospectively maintained electronic clinical database, comprehensive comparisons and correlative studies to monitor for metastasis and drug resistance and clinical outcomes in CRC across time can be carried out. Citation Format: Clarinda Chua, Rachel Ten, Thinzar Aung, Maricel Ang, Thein Htut Oo, Su Pin Choo, Matthew Ng, Iain Beehuat Tan. Longitudinal observational study to simultaneously evaluate multiple blood-based biomarkers to track the emergence of metastasis and drug resistance in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT320. doi:10.1158/1538-7445.AM2014-CT320

127 Background: The addition of trastuzumab to cisplatin and 5-fluorouracil or capecitabine has been shown to have superior survival benefit. In this study, the addition of trastuzumab to chemotherapy combination, S-1 (tegafur, gimeracil, oteracil potassium; TS-ONER) and cisplatin, a standard first line therapy for advanced gastric cancer in Japan, was evaluated for efficacy and safety. Methods: This was a single-arm, phase II trial recruiting patients with advanced HER-2 positive (IHC 3+ or FISH +) gastric adenocarcinoma who had not had prior systemic therapy. Patients included had measurable disease, ECOG 0-2, creatinine clearance >60ml/min, LVEF at least 50%. Patients accrued received cisplatin at 60mg/m2 on day 1 of each cycle, trastuzumab at 8mg/kg as loading dose followed by 6mg/kg on day 1 of each cycle and oral S-1 for 14 days ( dosing based on BSA), every 3 weeks. Treatment continued till progressive disease or unbearable toxicity. Primary endpoint was response rate (ORR) and secondary endpoints were PFS, OS, CBR and safety. The study was designed to distinguish a favorable ORR of 55% from a null rate of 30% at 5% significance level and 80% power. Results: A total of 30 patients were recruited. Median age was 61.9 years, 73% were males and 90% had no prior resection of primary tumor. 56.7% were Chinese, 23.3% Japanese and 20% Korean. One patient achieved complete response, 16 had partial response and 2 had stable disease >24 weeks (ORR 63%; CBR 70.4%). Three patients did not have evaluable disease. With a median follow-up of 7.2 months, the median PFS was 7.4 months with 67.7% free of disease progression at the 6-month mark. Median OS was 14.6 months. The most common AEs were anorexia (50%), fatigue (47%), diarrhea ( 47%), nausea (37%), neutropenia (33%), anemia (27%) and mucositis ( 27%). LVEF decreased

2566 Background: BAL101553, a pro-drug of the small molecule BAL27862, is a novel microtubule targeting agent (MTA) with cytotoxic and vascular disrupting properties. Pre-clinical data showed anti-proliferative activity in several in vitro and xenograft tumour models, including tumours refractory to conventional MTAs through diverse resistance mechanisms. Primary objectives of this FIH study were determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included the evaluation of PK, PD and anti-tumour activity. Methods: An accelerated titration dose-escalation design was used. Eligible patients (pts) with advanced solid tumours, who had failed standard therapy, received BAL101553 as a 2-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Adverse events (AEs) were assessed according to CTCAEv4. Disease response was assessed by RECIST 1.1 every 2 cycles. Results: 16 pts (7 male; median age 52 years; range 29-80) with solid tumours were treated at 4 dose levels (15, 30, 45 and 60 mg/m2). DLTs were observed at 60 mg/m2 and included rapidly reversible grade (G) 3 hypertension (HTN) and G3 reduced mobility/ dizziness. DLT criteria for HTN were subsequently modified. Frequent drug-related AEs were injection site reactions, nausea, vomiting (all G1-2), and G2-3 HTN (transient during the infusion; responding to nifedipine). One pt experienced G2 peripheral neuropathy at 60 mg/m2. PK analyses indicated conversion of BAL101553 to the active BAL27862, dose proportional exposure for both compounds and a half-life of BAL27862 in a range of 11 to 27 h. Preliminary tumour PD data comparing pre/post biopsies showed loss of CD34+ capillaries and focally decreased proliferation. A confirmed partial response was demonstrated in 1 pt with ampullary (pancreaticobiliary) cancer maintained on treatment for >16 cycles with intra-pt dose escalation. 2 pts (laryngeal and rectal cancer) demonstrated stable disease >16 weeks. Conclusions: BAL101553 is well tolerated up to 60 mg/m2 with evidence of anti-tumour activity. Dose escalation continues to determine the MTD. Clinical trial information: NCT01397929.

2608 Background: AR-12 (OSU-03012) is an oral celecoxib analogue lacking COX-2 inhibitory activity that inhibits pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1), AKT and impacts the endoplastic reticulum stress pathway. Preclinical studies indicate antitumor activity of AR-12 in various models and enhanced activity in combination. We completed a first in human clinical trial to determine its safety and tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RD). Secondary objectives included assessment of tumor response, pharmacokinetics (PK) and pharmacodynamics (PD) including food effect. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, and adequate organ function were recruited in a modified 3+3 dose-escalation study. Pts received a run-in dose of AR-12 to analyze PK-PD and food effect, followed by continuous daily (QD) dosing in 28-day cycles. A twice daily (BID) cohort was initiated based on safety data. PD analysis was performed in platelet-rich plasma (PRP) and paired tumor biopsies when feasible. Results: 35 pts received at least one dose of study drug; 30 were evaluable for dose limiting toxicities (DLT) at dose ranges 100-3200mg QD and 800-1600mg BID. No DLT were observed in the QD cohort; DLT in the BID cohort are listed in table 1. Drug-related events (NCI-CTCAE v3) included rash (G2-2pts; G3-1pt), fatigue (G2-2pts; G3-4pts), nausea (G2-7pts; G3-1pt) and bloating (G2-1pt). Cmax after single dose was dose-proportional but high PK variability was observed, likely due to inadequate disintegration and dissolution of the formulation in the stomach. At RD, partial GSK3ß inhibition in PRP after 4 hours suggests AKT-pathway modulation. Best response (RECIST v1.0) was stable disease >6 cycles for 2 pts. Conclusions: The RD based on safety data is 800mg BID. Signs of pathway modulation were observed in concordance with the expected mechanism of action but were short-lasting. Considering limited drug absorption and PK variability, a new formulation of the drug will be developed to overcome these limitations. Clinical trial information: NCT00978523. [Table: see text]

6 Background: Previous studies suggest that tumoral cfDNA is a potential biomarker in cancer. Methods: Prospective collection of samples from patients (pts) referred to a phase I trials unit, in 2 cohorts: “A”(manual isolation of cfDNA, Sep09-Dec10) and “B”(robotic isolation, Jan11-Sep11) and from 41 healthy volunteers (HV). CfDNA and tumor DNA from matched formalin-fixed paraffin-embedded (FFPE) tissue were isolated, quantified and analyzed for 238 oncogenic mutations (OM) in 19 oncogenes using Sequenom OncoCarta Panel 1.0. Mutation data were used for trial allocation when available. Statistical analyses used Pearson’s Chi-squared test and Mann-Whitney test. Results: 280 pts were included: breast (60; 21%), ovarian (44; 16%), and colorectal (42; 15%). 265 (95%) plasma and 194 (69%) FFPE samples were suitable for analysis. In 181 pts (65%) both samples were available for comparison. Median turnover time for cfDNA 7 days (range 5-14). Median [cfDNA] (concentration; ng/ml) in pts was higher than in HV (“A” 21 v 6.4;p