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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.

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

s: AACR Special Conference: Advances in Breast Cancer; October 17-20, 2015; Bellevue, WA Purpose: HER2+ and triple-negative (TN) breast cancers (BC) are associated with an aggressive course and poor prognosis, with currently available treatments yielding low response rates and decreased progression-free survival (PFS) due to a high relapse rate, rapid disease progression, and development of resistance. Hence, novel agents with efficacy and a tolerable safety profile are needed for this challenging patient (pt) population. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase (BTK), which is a crucial signaling molecule in the B-cell receptor pathway. It has demonstrated robust clinical activity in B-cell malignancies. In preclinical studies, ibrutinib inhibited tyrosine phosphorylation of ErbB and ErbB2 in HER2- positive BC cell lines, thereby suppressing AKT and MAPK signaling (Elias, 2013; Grabinski, 2014). Programmed death-ligand 1 (PD-L1) is a molecule associated with inhibition of antitumor T cell immunity (Zou, 2008; Keir, 2008), and is highly expressed in TNBC (Tessari, 2014; Mittendorf, 2014). Durvalumab (MEDI4736) is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 (IC50 of 0.1nM) and CD80/B7.1 (IC50 of 0.04 nM) (Ibrahim, 2015). Durvalumab has shown promising clinical activity with an acceptable safety profile across multiple solid tumors (Fury, 2014; Segal, 2014; Antonia, 2014). The combination of an anti–PD-L1 antibody and ibrutinib suppressed tumor growth in mouse models of solid tumors, and led to enhanced antitumor T-cell immune responses (Sagiv-Barfi, 2015). Based on these encouraging preclinical data, the PCYC-1135 trial ([NCT02403271][1]) was initiated to test the safety and efficacy of ibrutinib plus durvalumab in pts with relapsed/refractory (R/R) Stage III/IV BC (both HER2+ and TNBC), as well as non-small cell lung cancer (NSCLC), and pancreatic cancer. This abstract focuses on the BC cohort enrolling in the trial. Methods: A total of 130–160 pts (BC, NSCLC, and pancreatic) will be enrolled in this Phase 1b/2 study. Key eligibility criteria for the BC cohort include pathologically confirmed BC (HER2+ or TN), R/R disease (Stage III or IV) failing at least 2 prior therapies, measurable lesion by RECIST 1.1, and adequate hematologic, hepatic, and renal function. Key exclusion criteria include central nervous system involvement, antitumor therapy within 21 days of study initiation, prior treatment with ibrutinib or other BTK inhibitors, and/or anti-PD1, anti–PD-L1, anti–PD-L2, anti–CD137 or anti–CTLA-4 antibody, a history of allogeneic organ transplant, or treatment with a strong cytochrome P4503A inhibitor. The primary objectives are safety, tolerability, and efficacy as assessed by overall response rate. Secondary endpoints are disease control rate, duration of response, PFS, overall survival, and pharmacokinetics and pharmacodynamic assessments of the combination. The Phase 1b will assess dose-limiting toxicities (DLTs) and will determine the recommended phase 2 dose (RP2D) of ibrutinib plus durvalumab. The starting dose level of ibrutinib is 560 mg daily, with the potential for subsequent dose level reductions if DLTs occur, in combination with durvalumab 10 mg/kg IV every 2 weeks in 28-day cycles until DLT or disease progression. Enrollment in phase 2 will commence at the RP2D, accruing a total of 130–160 pts (Phase 1b + Phase 2). Ibrutinib and durvalumab will be administered until unacceptable toxicity or disease progression. Enrollment began in March 2015. Citation Format: Drew W. Rasco, Erkut Borazanci, Martin Guiterrez, David Hong, Ahmed Tawashi, Jennifer Lin, Isaiah W. Dimery, Mark Fosdale. Ibrutinib in combination with durvalumab (MEDI4736) in patients with relapsed or refractory HER2-positive or triple-negative breast cancer: A phase 1b/2 multicenter study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B42. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02403271&atom=%2Fmolcanres%2F14%2F2_Supplement%2FB42.atom