A phase I/II, multicenter, open-label study of REGN5668 (mucin [MUC]16 x CD28 bispecific antibody [bsAb]) with cemiplimab (programmed death [PD]-1 Ab) or REGN4018 (MUC16 x CD3 bsAb) in recurrent ovarian cancer (rOVCA).

TPS5602 Background: There is a high unmet need in rOVCA treatment, with 14,000 deaths/year in the US and a 30%‒40% 5-year overall survival rate in patients (pts) with advanced disease. REGN5668 and REGN4018 are human IgG4-based bsAbs that bridge ovarian MUC16+ tumor cells to CD28 and CD3, respectively, on T-cells to stimulate cytotoxicity. Cemiplimab is a human monoclonal Ab that blocks PD-1 binding to PD-ligand(L)1 and PD-L2. REGN5668 demonstrated increased preclinical anti-tumor activity with PD-1 inhibition or REGN4018 relative to each monotherapy. A Phase I/II study of REGN4018 alone or with cemiplimab is ongoing. Methods: This first-in-human study (NCT04590326) will assess safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN5668 with cemiplimab (Module 1) or REGN4018 (Module 2) in pts with rOVCA. Key inclusion criteria include histologically confirmed diagnosis of advanced epithelial ovarian (except carcinosarcoma), fallopian tube, or primary peritoneal cancer; serum CA-125 level ≥2x upper normal limit; ≥1 prior-line of platinum-based therapy; prior treatment with or intolerance to available standard-of-care therapy. Exclusion criteria include recent biologic therapy ( < 5 half-lives or 28 days, whichever is longer, except < 3 half-lives for bevacizumab or other nonimmunomodulatory Abs with half-lives > 7 days); approved conventional therapy (except biologics or immunotherapy) < 3 weeks (wks) or investigational agents < 4 wks prior to first study dose; and anti–PD-L1 therapy < 5 half-lives prior to first study dose. This two-phase study includes dose escalation (a 4+3 design modified from 3+3) and expansion phases. In Module 1, ≤84 pts will receive 3–4 wks of REGN5668 monotherapy lead-in at assigned intravenous (IV) weekly (QW) dose levels, followed by REGN5668 QW combined with cemiplimab IV every 3 wks. In Module 2, ≤106 pts will receive 4–5 wks of REGN4018 QW IV lead-in, followed by REGN4018 full QW dose combined with REGN5668 at initial and full assigned QW doses. In expansion, REGN5668+cemiplimab and REGN5668+REGN4018 combination regimens will each recruit 20 pts in stage 1 and 30 pts in stage 2 using a Simon two-stage design. In escalation, primary endpoints are dose-limiting toxicities, serious and treatment-emergent adverse events (TEAEs), deaths, laboratory abnormalities (Grade ≥3), concentrations of REGN5668 in serum alone and in each combination regimen; key secondary endpoint is objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. In expansion, primary endpoint is ORR by RECIST 1.1 for each combination; key secondary endpoints are TEAEs, serious AEs, deaths. Key exploratory endpoints are correlation between clinical efficacy endpoints and baseline protein expression levels of MUC16 and PD-L1. Clinical trial information: NCT04590326.

AB0381 THE UTILITY OF HYDROXYCHLOROQUINE (HCQ) THERAPY FOR TWO YEARS AS A SPARING CORTICOSTEROID AGENCY IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Background:Prednisolone (PSL) and HCQ are key drugs in the therapy of SLE. However, since PSL induce many harmful adverse events, PSL is preferred to be reduced especially in the maintenance therapy. The efficacy of HCQ for reducing the dose of PSL has not been revealed yet. So, we focused on the cessation of PSL under the treatment of HCQ with conventional SLE therapy.Objectives:The aim of this study is to evaluate the efficacy and the safety of HCQ as co-treatment in the standard therapy of SLE.Methods:SLE patients (n=30) under the maintenance therapy were enrolled in this study. Dose of PSL, titer of anti-DNA antibody, WBC count, serum complement and SLE disease activity index (SLEDAI) were examined retrospectively at 0 and 12 months after administration of HCQ.Results:Baseline patient-characteristics are as follows (mean±S.E); the age of patients was 54.4±3.2 years old, 21 patients (70%) were female, the disease duration was 108.5±25.2 months, SLEDAI was 4.0±0.9, the dose of PSL was 10.3±1.7 mg/day, the titer of anti-DNA antibody was 7.3±1.8 IU/ml, C3 was 85±4.3 mg/dl and C4 was 18±1.6 mg/dl.The mean dose of PSL was reduced with statistically significance (pre-administration of HCQ:10.3±1.7 mg/day, 24 months after administration of HCQ:2.2±0.3 mg/day,p<0.0001). Furthermore, in this observation period, 6 patients could achieve the cessation of PSL.SLEDAI was also significantly reduced (4.0±0.9 vs 1.0±0.3,p<0.01).There was no statistical significance between before treatment by HCQ and after treatment in the titer of anti-DNA antibody (7.3±1.8 vs 2.8±1.6 IU/ml,p=0.06), WBC count (6208±4.9 vs 5096±3.3 /μl,p=0.06) and serum complement level (C3 85±4.3 mg/dl vs 89±4.0 mg/dl,p=0.52, C4 18±1.6 mg/dl vs 19±1.4 mg/dl,p=0.45). Relapse of SLE was clarified in only one patient.As for adverse events (AEs), Severe bacterial infection (n=4), herpes zoster (n=1) and patellar tendon rupture (n=1) were revealed. All cases of the AEs were fully recovered.Conclusion:Our study suggested that co-treatment with HCQ on standard SLE therapy could be enable to prevent the flare of SLE and reduce the dose of PSL with statistical significance. In some cases, we could achieve the cessation of PSL treatment.References:None.Disclosure of Interests:None declared

Phase I trial of nab-paclitaxel administered concurrently with radiotherapy in patients with locally advanced inoperable pancreatic adenocarcinoma (ART in LAP).

e16796 Background: Locally advanced pancreatic adenocarcinoma (LAPC) carries a poor prognosis with median overall survival of 12-18m. The optimal treatment is controversial. Nab-paclitaxel is active in advanced pancreatic cancer and has exhibited radio-sensitising anti-tumour efficacy. Methods: We conducted an investigator-initiated open-label, phase-I dose escalation trial of nab-paclitaxel with standard external beam radiotherapy (EBRT). All patients had biopsy-proven, untreated, localised, inoperable pancreatic adenocarcinoma; Patients received nab-paclitaxel on a weekly schedule for 6 weeks, concurrently with EBRT. A 3+3 cohort design was employed, with doses of nab-paclitaxel increasing from 25 mg/m2 (cohort 1), to 50 mg/m2 (cohort 2), 75 mg/m2 (cohort 3) and 100 mg/m2 (cohort 4). This principal objective of the trial was to establish the maximum tolerated dose (MTD) of nab-paclitaxel given concurrently with radiotherapy. Secondary objectives included safety and efficacy evaluation, including response rate, median PFS, median and 1- year OS. Results: Fourteen patients were recruited to the study, with a median age of 69 (range 40-86). 69% had a head or neck of pancreas tumour. Majority of patients had grade 1 or 2 toxicities with nausea (92%), fatigue (69%), diarrhoea (54%) and vomiting (54%) being the most common. Three patients were recruited in each of the first three cohorts, without any dose limiting toxicities (DLT). In cohort 4, DLT of febrile neutropenia and enterocolitis was observed in patient 1. The cohort was expanded with a subsequent DLT of febrile neutropenia and enterocolitis observed in patient 5. Both DLT events lead to death (grade 5). The MTD and recommended phase II study dose has been established as 75mg/ m2. The disease control (PR and SD) rate was 67%, median PFS 4.7 months (95% CI 2.5-27.5), 1 year OS 43% and median OS 11.4 months (95%CI 6.37-25.2). Conclusions: The combination of weekly nab-paclitaxel and fractionated radiation was generally well-tolerated at doses of nab-paclitaxel below 100 mg/m2. There were two treatment related DLTs leading to death in the nab-paclitaxel 100 mg/m2 cohort. The MTD and recommended phase II study dose for nab-paclitaxel combined with radiation therapy in the treatment of LAPC is 75mg/m2. Clinical trial information: ACTRN12613001013752 .

Discordant Dose-Dependent Metabolic Effects of Eicosapentanoic Acid in Diet-Induced Obese Mice

Obesity is a widespread epidemic that increases the risk for several metabolic diseases. Despite several beneficial health effects of eicosapentaenoic acid (C20:5n-3, EPA), previous studies have used very high doses of EPA. In this study, dose-dependent effects of EPA on metabolic outcomes were determined in diet-induced obese mice. We used B6 male mice, fed high-fat diet (HF, 45% kcal fat) or HF diet supplemented with 9, 18, and 36 g/kg of EPA-enriched fish oil for 14 weeks. We conducted metabolic phenotyping during the feeding period, and harvested tissues and blood at termination. Only mice fed 36 g/kg of EPA significantly (p < 0.05) lowered body weight, fat content and epididymal fat pad weight, compared to HF. Both 18 and 36 g/kg doses of EPA significantly increased glucose clearance and insulin sensitivity, compared to HF or 9 g/kg of EPA. Locomotor activity was significantly increased with both 18 and 36 g/kg doses of EPA. Interestingly, all doses of EPA compared to HF, significantly increased energy expenditure and oxygen consumption and significantly reduced serum insulin, leptin, and triglycerides levels. These results demonstrate weight- and adiposity-independent metabolic benefits of EPA, at doses comparable to those currently used to treat hypertriglyceridemia.

Outcomes in patients (pts) with advanced renal cell carcinoma (aRCC) who discontinued (DC) first-line nivolumab + ipilimumab (N+I) or sunitinib (S) due to treatment-related adverse events (TRAEs) in CheckMate 214.

581 Background: The phase 3 CheckMate 214 trial demonstrated superior efficacy for N+I vs S in aRCC, although more patients discontinued N+I compared with S due to TRAEs. This is a post hoc analysis of outcomes in pts who DC N+I or S due to TRAEs. Methods: Untreated pts with clear cell aRCC were randomized 1:1 to N 3 mg/kg + I 1 mg/kg Q3Wx4 (induction) and then N 3 mg/kg Q3W (maintenance), or S 50 mg daily for 4 wk on, 2 wk off (6-wk cycles). This analysis includes all pts who DC due to TRAEs reported during extended follow-up (≤100 d after last study dose). Results: Of 550 N+I randomized pts, 135 (25%) DC due to TRAEs, most commonly increased ALT, diarrhea, and increased AST (all 3%); 64 (12%) of 535 S randomized pts DC due to TRAEs, most commonly increased ALT, diarrhea, and pancreatitis (all 1%). In N+I pts who DC due to TRAEs, 47% DC during N+I induction, 7% completed induction but no N maintenance, and 46% completed induction and received N maintenance (median [range] 8 [1–47] doses). At 30-mo minimum follow-up, ORR per investigator, CR rate, and 24-mo OS rate were higher in pts who DC N+I vs S due to TRAEs. Outcomes in pts who DC S due to TRAEs were similar to those in all S ITT pts and worse than in N+I pts who DC due to TRAEs (Table). At 24 mo, 42% of pts who DC N+I due to TRAEs were alive and free from second-line therapy. Consistent outcomes were seen in pts who DC N+I due to TRAEs across IMDC risk groups (data to be presented). Pts who DC N+I due to TRAEs experienced more immune-related select TRAEs and received more high-dose steroids (≥40 mg prednisone daily or equiv.), but times to onset and resolution and resolution rates of select TRAEs were similar vs all treated N+I pts. Conclusions: Discontinuation of first-line N+I due to TRAEs did not result in impaired outcomes, and a high proportion of pts remain alive and free from second-line therapy. Clinical trial information: NCT02231749. [Table: see text]