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Baseline (screening) vs treatment cycle 2 (P=.06; paired t test). For patient 5, baseline data were not available.

Purpose:Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial.Patients and Methods:Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc.Results:One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25–7.20 months)/9.9 (6.74–12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06–23.49 months)]. Overall response rate (95% CI) was 18% (8.6%–31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 + CD8+/CD4+ cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67+ CD8+ T-cell values were higher in responders than in nonresponders.Conclusions:The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.

Percentage lymphocyte subset Ki67+. All patient visits are binned by treatment cycle. Data at baseline and treatment cycle 3 were compared using the Wilcoxon signed rank test. All available data are illustrated; however, statistical comparisons were performed only for data available at both baseline and treatment cycle 3 (n=29).

T-Cell Tumor Infiltration in Tissue-Matched Baseline (screening) and On-Treatment Metastatic Tumors (arm B parts 1 and 2)

Investigator-assessed PFS and OS in patients with PD-L1 expression cutoff of 1% (A, B) or 5% (C, D). HR, hazard ratio; mo, months; OS, overall survival; PD-L1, programmed cell death ligand-1; PFS, progression-free survival.

Patients were enrolled in Arm B Part 1 after the safety oversight committee deemed Arm A Part 1 safe. DRC, data review committee; LAPC, locally advanced pancreatic cancer; MPC, metastatic pancreatic cancer; RP2D, recommended Part 2 dose.

Concentrations of CXCL10 (A) and sIL2Rα (B) at baseline and peak on-treatment values. Investigator-assessed PFS in patients with high or low serum cytokines CXCL10 (C) and sIL2Rα (D). CXCL10, interferon gamma-induced protein 10; mo, months; NE, not estimable; NR, nonresponder; PFS, progression-free survival; R, responder; sIL2Rα, soluble form of interleukin 2 receptor alpha; Tx, treatment.

Data Tables

Purpose: Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial. Patients and Methods: Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc. Results: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25–7.20 months)/9.9 (6.74–12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06–23.49 months)]. Overall response rate (95% CI) was 18% (8.6%–31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 Conclusions: The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.

Purpose: To evaluate safety and preliminary efficacy of metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with newly diagnosed metastatic pancreatic cancer (MPC). Methods: A total of 12 treatment-naive patients (aged 18–65 years, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤1) with MPC received 5-fluorouracil 180 mg/m2 per day (days 1–14 continuous infusion); nab-paclitaxel 75 mg/m2, leucovorin 20 mg/m2, and oxaliplatin 40 mg/m2 (days 1, 8, and 15); and bevacizumab 5 mg/kg (days 1 and 15) administered intravenously in each 28-day cycle. The primary end-point was incidence of dose-limiting toxicities (DLTs) in cycle 1. Safety was further evaluated as a secondary end-point; preliminary efficacy was also examined. Results: Two DLTs (grade 3 anemia requiring transfusion and grade 3 mucositis unresponsive to treatment within 4 days of onset) were observed in one of six patients enrolled in dose cohort 1. Cohort 1 was expanded from 6 to 12 patients to further evaluate safety, per the investigators' recommendation. All patients discontinued treatment. The most common grade ≥3 adverse events were abdominal pain, fatigue, mucositis, and decreased neutrophil count. Objective response rate was 33% (four partial responses). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (95% confidence interval [CI], 1.7–11.3) and 9.9 (95% CI, 4.4–13.2) months, respectively; 1-year PFS and OS rates were 12.2% (95% CI, 0.7–40.8) and 38.9% (95% CI, 12.6–65.0). Conclusion: FABLOx is feasible and tolerable in patients newly diagnosed with MPC. However, preliminary efficacy data are inconclusive for continued investigation in a phase II trial.

Assess safety and efficacy of nivolumab plusFifty chemotherapy-naive patients receivedOne DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25-7.20 months)/9.9 (6.74-12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06-23.49 months)]. Overall response rate (95% CI) was 18% (8.6%-31.4%). Median PFS/OS was 5.5/9.7 months (PD-L15%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67The safety profile of nivolumab plus

BACKGROUND: MF is characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, marrow fibrosis, splenomegaly, and shortened survival. Fedratinib (FEDR) is an oral, selective JAK2 inhibitor approved in the United States (US) for treatment (Tx) of INT-2 or high-risk MF. Ruxolitinib (RUX) is a JAK1/2 inhibitor approved in the US and European Union for Tx of INT- or high-risk MF. Clinical experience indicates that weight gain during RUX Tx is both common and substantial (mean increase ~4 kg from baseline [BL] in the COMFORT-I and COMFORT-II studies); begins during early Tx (~6-8 weeks from initiation) and continues throughout the course of Tx; and cannot be solely attributable to resolution of MF symptoms (eg, early satiety, abdominal discomfort) or splenomegaly (Mesa 2015; Sapre 2019; Molle 2020). The impact of FEDR on weight and metabolic parameters is of interest. FEDR was investigated in the randomized, placebo (PBO)-controlled, phase III JAKARTA trial in patients (pts) with JAK-inhibitor-naïve MF, and in the single-arm, phase II JAKARTA2 trial in pts with MF previously treated with RUX. OBJECTIVE: Evaluate changes in weight, BMI, and metabolic parameters in pts treated with FEDR 400 mg/day. METHODS: JAKARTA enrolled pts with INT-2 or high-risk primary or post-ET/post-PV MF, platelet counts ≥ 50 ×109/L, palpable splenomegaly (≥ 5 cm below LCM), and ECOG PS ≤ 2. Pts were randomized 1:1:1 to FEDR 400 mg, FEDR 500 mg, or PBO, administered once-daily for at least 6 continuous 28-day Tx cycles (ie, 24 weeks). This analysis focuses on pts randomized to FEDR 400 mg/day (approved starting dose) or PBO. We assessed changes from BL in weight, BMI, albumin, fasting glucose, and systolic and diastolic blood pressure (SBP and DBP) at the end of cycle 6 (EOC6; PBO pts could crossover to FEDR after EOC6). Reported changes from BL at EOC6 are for pts who completed 6 Tx cycles. As a supporting analysis, we assessed changes in these parameters for pts in JAKARTA2, who all received FEDR 400 mg/day (starting dose). RESULTS: In JAKARTA, 96 pts received FEDR 400 mg and 95 pts received PBO. Median age at BL was 63 years (range 39-86) in the FEDR arm and 66 (27-85) in the PBO arm, and mean [±SD] spleen volumes were 2755 [1353] mL and 2928 [1484] mL, respectively. In the FEDR arm, mean weight at BL was 69.4 kg, and remained relatively unchanged during FEDR Tx, increasing by 0.8 kg from BL to EOC6 (Figure). In the PBO arm, mean weight decreased by 0.1 kg from BL (68.6 kg) to EOC6. Mean BMI increased nominally by 0.3 in the FEDR arm (BL 24.0) and was unchanged from BL (24.3) in the PBO arm. In the FEDR arm, mean albumin level increased slightly by 0.24 g/dL from BL (4.14 g/dL) to EOC6, and fasting glucose was unchanged from BL (5.5 mmol/L). No clinically significant changes were observed in SBP or DBP during FEDR Tx, which were 124.5 and 70.6 mmHg at BL, respectively, and increased nominally at EOC6 by 1.7 and 0.1 mmHg. In the PBO arm, mean albumin level was 4.07 g/dL at BL and decreased by 0.09 g/dL at EOC6, fasting glucose was 5.6 mmol/L and decreased by 0.1 mmol/L, SBP was 124.3 mmHg and increased by 1.3 mmHg, and DBP was 70.6 mmHg and decreased by 1.3 mmHg. JAKARTA2 included 97 pts with advanced MF previously treated with RUX. Median age at study entry was 67 years (range 38-83) and mean [±SD] spleen volume was 3095 [1459] mL. At BL, mean weight was 73.5 kg and BMI was 25.5; these decreased by 0.6 kg and 0.2, respectively, by EOC6. From BL to EOC6, mean albumin, fasting glucose, SBP, and DBP changed by +0.39 g/dL (BL 3.94 g/dL), -0.6 mmol/L (BL 6.6 mmol/L), +3.8 mmHg (BL 124.1 mmHg), and +2.9 mmHg (BL 66.7 mmHg), respectively. Median spleen volume change from BL to EOC6 with FEDR 400 mg was -40% in JAKARTA and -34% in JAKARTA2. There was no apparent correlation between changes in weight and spleen volume in pts treated with FEDR 400 mg in either trial. CONCLUSIONS: Disproportionate weight gain not correlating with MF symptom resolution is a concern with long-term RUX Tx. In JAKARTA, FEDR did not meaningfully increase pts' weight or BMI after 6 Tx cycles. Modest increases in albumin compared with BL suggest improved nutritional status during FEDR Tx, and there were no clinically relevant changes in fasting glucose or BP after 6 FEDR Tx cycles. Changes in weight and metabolic parameters in JAKARTA2 support findings with FEDR 400 mg from JAKARTA. Unlike observations in pts treated with RUX (Mesa 2015), spleen volume reductions during FEDR Tx were not associated with weight increases. Disclosures Cavalli: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Banerjee:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy.

Purpose: To evaluate safety and preliminary efficacy of metronomic 5-fluorouracil plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with newly diagnosed metastatic pancreatic cancer (MPC). Methods: A total of 12 treatment-naive patients (aged 18–65 years, Eastern Cooperative Oncology Group performance status [ECOG PS] ≤1) with MPC received 5-fluorouracil 180 mg/m2 per day (days 1–14 continuous infusion); nab-paclitaxel 75 mg/m2, leucovorin 20 mg/m2, and oxaliplatin 40 mg/m2 (days 1, 8, and 15); and bevacizumab 5 mg/kg (days 1 and 15) administered intravenously in each 28-day cycle. The primary end-point was incidence of dose-limiting toxicities (DLTs) in cycle 1. Safety was further evaluated as a secondary end-point; preliminary efficacy was also examined. Results: Two DLTs (grade 3 anemia requiring transfusion and grade 3 mucositis unresponsive to treatment within 4 days of onset) were observed in one of six patients enrolled in dose cohort 1. Cohort 1 was expanded from 6 to 12 patients to further evaluate safety, per the investigators' recommendation. All patients discontinued treatment. The most common grade ≥3 adverse events were abdominal pain, fatigue, mucositis, and decreased neutrophil count. Objective response rate was 33% (four partial responses). Median progression-free survival (PFS) and overall survival (OS) were 5.6 (95% confidence interval [CI], 1.7–11.3) and 9.9 (95% CI, 4.4–13.2) months, respectively; 1-year PFS and OS rates were 12.2% (95% CI, 0.7–40.8) and 38.9% (95% CI, 12.6–65.0). Conclusion: FABLOx is feasible and tolerable in patients newly diagnosed with MPC. However, preliminary efficacy data are inconclusive for continued investigation in a phase II trial.

OBJECTIVES: Visualization in state sequence data has been developed extensively through an R package described in Gabadinho et al. (2011). Graphics depicting states prevalent at each cross section in time can be generated for all data as well as for covariate level sets for datasets with a large number of subjects with state transitions over time. Special longitudinal sequence sets can also be carved out using similarity measures across sequences. In our work, we believed there may be latent informative images inherent in data on changes in cancer states (degrees of response, progressions, and deaths). We obtain a longitudinal as well as a cross-sectional informative image through a novel heuristic grounded in the framework of hierarchical clustering. METHODS: We used iconic known images, stripped them of all ordering information, and attempted to recover the known latent image underlying the randomly permuted data using our heuristic as well as other alternative methods such as those in Sakai et al. (2014). RESULTS: Results validate our methods. The method is demonstrated through a visual representation of changes in cancer states for two induction therapies in a cancer trial. A further application to a two-way ordering of gene sample heat maps are also presented. CONCLUSIONS: When cancer state transition graphics for competing therapies are juxtaposed, there can be a quick read of early versus late response to therapy, the depth and duration of response as well as a rough gauge of events such as progression and death. This is a good complement to quantitative inferences. For gene expression data, we hope that our methods will bring out finer distinctions in addition to presenting gross patterns in the data like those seen using prevalent methods.

298 Background: Chemotherapy may work synergistically with immune checkpoint inhibitors by increasing tumor antigen exposure. This 2-part phase I study assessed safety and efficacy of Nivo + nab-P + Gem in APC. Methods: Treatment-naive patients (pts) with APC (locally advanced or metastatic) received nab-P 125 mg/m2 + Gem 1000 mg/m2 on d 1, 8, and 15 + Nivo 3 mg/kg on d 1 and 15 of each 28-d cycle until disease progression (PD), unacceptable toxicity, or withdrawal. Pts could continue Nivo alone beyond initial PD. Part 1 assessed dose-limiting toxicities (DLTs) and determined the recommended Part 2 dose; Part 2 (expansion phase) further assessed safety. The primary endpoints were DLTs (Part 1) and safety and tolerability (Parts 1 and 2). Key secondary endpoints were response rates, progression-free survival (PFS), and overall survival (OS). Results: As of July 13, 2018, 50 pts with APC were treated: 6 in Part 1; 44 in Part 2. The median age was 67.5 years; 56% were male; 62% had an ECOG PS 1. Of 40 pts with available data, 12 (24%) had ≥ 1% and 6 (12%) had ≥ 5% PD-L1 expression at baseline (data missing for 10 pts). The median follow-up was 11.3 mo. In Part 1, 1 DLT (hepatitis, as evidenced by grade 3 elevated liver function tests; suspected to be related to nab-P + Gem) was reported. In Parts 1 and 2, 48 pts (96%) had ≥ 1 grade 3/4 TEAE; 7 (14%) discontinued treatment due to a TEAE. Most common (> 10%) grade 3/4 TEAEs of special interest were anemia (36%), neutropenia (36%), gastrointestinal events (24%), hepatic toxicity (22%), peripheral neuropathy (16%), thrombocytopenia (12%), and colitis (12%). One grade 5 TEAE, respiratory failure (most likely pneumonitis), was reported. The table shows treatment responses. Of 7 pts (14%) who continued Nivo beyond initial PD, 4 achieved disease control. The median PFS was 5.5 mo (6-mo PFS rate, 47%). The median OS was 9.9 mo (6-mo OS rate, 73%). Conclusions: Combining Nivo with nab-P + Gem is feasible in pts with APC: 1 DLT was reported, and no unexpected safety signals were detected. Clinical trial information: NCT02309177. [Table: see text]

Dennis E Doherty1, Donald P Tashkin2, Edward Kerwin3, Barbara A Knorr4, Tulin Shekar4, Sibabrata Banerjee4, Heribert Staudinger41Division of Pulmonary, Critical Care, and Sleep Medicine, University of Kentucky, Lexington, KY, 2David Geffen School of Medicine at UCLA, Los Angeles, CA, 3Clinical Research Institute of Southern Oregon, Medford, OR, 4Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USARationale: The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 µg, MF/F 200/10 µg, MF 400 µg, F 10 µg, or placebo. The trial’s co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV1) over 0–12 hours (AUC0-12 h FEV1) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV1 with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George’s Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation.Results: The largest improvements in AUC0-12 h FEV1 were observed with MF/F 400/10 µg and MF/F 200/10 µg. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV1, for which effects were further investigated, excluding subjects whose AM FEV1 data were incorrectly collected after 2 days from the last dose of study treatment. Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments. At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported. No unexpected AEs were observed. Overall, 90 subjects reported AEs considered to be treatment-related, the most common of which were lenticular opacities, dysphonia, and oral candidiasis.Discussion: In conclusion, MF/F treatments improved lung function and respiratory health status, reduced exacerbations, and were well tolerated in subjects with moderate-to-very severe COPD.Keywords: COPD, FEV1, spirometry, exacerbation, inhaled corticosteroid, bronchodilator

This book was published by the SAS Institute in the SAS Press Series. The target audience could be any statistician with a reasonable understanding of linear regression and linear models who is som...