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Background: ENKTL is a highly aggressive NHL related to Epstein-Barr virus, with a higher incidence in Asia. Patients with r/r-ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-PD-1 antibody represented a favorable treatment for rr-ENKTL. ORIENT-4 trial demonstrated Sintilimab was effective and well tolerated in r/r-ENKTL. The efficacy of Chidamide, an oral HDACi was reported on rr-ENKTL(CHIPEL trial, 2017 ASH). Here we present preliminary results of Sintilimab plus Chidamide for r/r-ENKTL. Methods: This trial enrolled eligible patients with histologically confirmed r/r-ENKTL failing from asparaginase-based regimen; ECOG performance status ≤ 2; adequate organ function and bone marrow function; and at least one measurable or evaluable lesion. This study consisited of a Phase Ib (dose escalation) portion followed by a Phase II expansion portion. In the Phase Ib, a standard "3+3" design was utilized to identify the MTD, DLT and recommended Phase II dosage (RP2D) of Chidamide plus Sintilimab. In the phase II portion, patients received 6 cycles of Sintilimab (200 mg) plus Chidamide (RP2D) every 3 weeks. Patients with complete response (CR) or partial response (PR) received up to 1 year. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIL 2017 criteria. Key secondary endpoints included TTR, DOR,PFS,OS and safety. Adverse events (AEs) were defined according to CTCAE 5.0. Pretreatment formalin-fixed, paraffin-embedded (FFPE) tumor samples were obtained. Samples were tested using Dako PD-L1 22C3. PD-L1 protein expression was determined using tumor proportion score (TPS) and combined positive score (CPS). CPS ≥1 was considered positive. All patients' blood samples were collected for ctDNA assessment before treatment in each of cycles. ctDNA samples were analyzed by capture-based NGS targeting 475 lymphoma- and cancer- relevant genes. This trial was registered at ClinicalTrials.gov (NCT 03820596) Results: From March 2019 to May 2020, 41 patients were screened and 37 eligible patients were enrolled from 5 institutions. Median age 48 years (range, 20-72), 27 (73.0%) male, 26 (70.3%) patients with Stage IV of disease at screening, 20 (54.1%) patients with PINK-E score ≥ 3 points, 16 (43.2%) patients received ≥ 2 lines of prior systemic therapy. In Phase Ib , no MTD or DLT events were observed, RP2D of chidamide was 30 mg twice a week. Of 36 response evaluable patients, 21 (58.3%) achieved response including 16 (44.4%) patients with CR and 5 (13.9%) with PR(Figure 1). The median time to initial response was 6.0 weeks (5.0-12.4w). The median DOR time was 9.2+ months (1.3 -14.5+m) (Figure 2). The median follow-up time was 7.3 (0.9-16.1) months. Estimated 1-year OS rate was 79.1%, 1-year PFS rate was 66.0%. 19 (51.3%) patients remained on treatment,18 (48.7%) patients had discontinued from study treatment (16 for PD, 1 for AEs, 1 for personal reasons). The OS and PFS of patients with CR/PR is significantly superior to patients with SD/PD. Estimated 1-year OS rate for CR/PR and SD/PD was 95.0% and 51.9% (P<0.001), 1-year PFS rate was 95.0% and 31.2%, respectively (P<0.001). Among 27 patients with available FFPE tissue specimens, PD-L1 expression in more than 50% and 10% of tumor cells were observed in 12 (44.4%) and 8 patients (29.6%). The median value of CPS was 40.0, patients with PD-L1 CPS≥30 exhibited benefit more from treatment. Dynamics ctDNA assay is in progress, data in detail will be reported at the ASH conference. 21 (56.8%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were neutropenia (51.4%), thrombocytopenia (45.9%), transaminase increased (29.7%), nausea (24.3%). The most frequent Grade (G) ≥3 TRAEs were neutropenia (16.2%) and thrombocytopenia (10.8%). Immune-related AEs were reported in 16 (43.2%) patients including a G4 exfoliative dermatitis, and the most common irAEs were G1 hypothyroidism and rash. No death was related to the study. Conclusion: Sintilimab plus Chidamide showed manageable safety profile and yielded effective antitumor activity, durable response in patients with r/r-ENKTL for the first time. It is a promising therapeutic option for this population, especially for those with CPS≥30. Epigenetic strategies synergize with anti-PD-1 antibody maybe enhanced antitumor responses to r/r-ENKTL, further investigation is warranted. Disclosures No relevant conflicts of interest to declare.

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BackgroundTriple-negative breast cancer (TNBC) is associated with an aggressive clinical course due to the lack of therapeutic targets. Therefore, identifying reliable prognostic biomarkers and novel therapeutic targets for patients with TNBC is required. Proline, glutamic acid, leucine rich protein 1 (PELP1) is a novel steroidal receptor co-regulator, functioning as an oncogene and its expression is maintained in estrogen receptor (ER) negative breast cancers. PELP1 has been proposed as a prognostic biomarker in hormone-related cancers, including luminal-type breast cancers, but its significance in TNBC has not been studied.MethodsPELP1 immunoreactivity was evaluated using immunohistochemistry in 129 patients with TNBC. Results were correlated with clinicopathological variables including patient’s age, tumor size, lymph node stage, tumor grade, clinical stage, histological type, Ki-67 LI, as well as clinical outcome of the patients, including disease-free survival (DFS) and overall survival (OS).ResultsPELP1 was localized predominantly in the nuclei of carcinoma cells in TNBC. With the exception of a positive correlation between PELP1 protein expression and lymph node stage (p = 0.027), no significant associations between PELP1 protein expression and other clinicopathological variables, including DFS and OS, were found. However, when PELP1 and Ki-67 LI were grouped together, we found that patients in the PELP1/Ki-67 double high group (n = 48) demonstrated significantly reduced DFS (p = 0.005, log rank test) and OS (p = 0.002, log rank test) than others (n = 81). Multivariable analysis supported PELP1/Ki-67 double high expression as an independent prognostic factor in patients with TNBC, with an adjusted hazard ratio of 2.020 for recurrence (95 % CL, 1.022–3.990; p = 0.043) and of 2.380 for death (95 % CL, 1.138–4.978; p = 0.021).ConclusionsWe found that evaluating both PELP1 and Ki-67 expression in TNBC could enhance the prognostic sensitivity of the two biomarkers. Therefore, we propose that PELP1/Ki-67 double high expression in tumors is an independent prognostic factor for predicting a poor outcome for patients with TNBC.

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Maximum allowable wellhead pressure is an effective indicator for both site safety control and government regulation of CO2 geological storage projects. In many carbon capture and storage (CCS) projects, the injection rate may also be set as an obligatory objective. For such a problem of multi‐objective design, no systematic design methodology has been opened in the publicly available literature. Although a numerical simulator can be employed to obtain the wellhead pressure through a series of trial processes of calculations, this will usually need more model parameters and a large number of computations, especially when there are more reservoirs. In this study, an extensible methodological framework for designing a maximum allowable wellhead pressure for CO2 injection was developed. The methodology is based on a thermal‐hydraulic coupling model of wellbore and reservoir flows suitable for arbitrary number of reservoirs. The new methodology can automatically accommodate multiple design objectives, such as site stability and total injection rate. As a result of explicit solutions employed, the methodology has the advantage of less computation and high speed. Using this method, we recommended a maximum allowable wellhead pressure of 13.0 MPa for the Shenhua CCS demonstration project in China, which has been accepted by the expert committee of the project. The large amount of verification data and four‐year successful injections in the project have proved the effectiveness of the new method. © 2016 Society of Chemical Industry and John Wiley & Sons, Ltd.

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