Michele Gargano

Phase Ib study of PGG beta glucan in combination with anti-MUC1 antibody (BTH1704) and gemcitabine for the treatment of advanced pancreatic cancer.

TPS493 Background: Mucin 1 (MUC1) is a tumor associated membrane-bound glycoprotein that promotes oncogenesis through promotion of epithelial cell polarity loss, anti-apoptosis, and hypoxia driven angiogenesis. MUC1 overexpression is associated with aggressive behavior and poor outcomes in pancreatic ductal adenocarcinoma (PDAC), and increased resistance to gemcitabine (G) in vitro. BTH1704 (BTH) is a humanized monoclonal antibody (MAb) targeting aberrantly glycosylated MUC1. Imprime PGG (PGG) is a soluble yeast-derived b 1,3/1,6 glucan that binds complement receptor 3 (CR3) on innate immune cells priming them to exert anti-tumor activity against complement (iC3b) opsonized tumor cells. Following incubation of PGG with whole blood from healthy subjects, variability in PGG binding to neutrophils and monocytes has been observed, with higher binding and functional changes correlating with higher levels of endogenous anti-b glucan antibodies. BTH binds to antigens (MUC1), leading to iC3b opsonization of tumor...

Abstract A26: Imprime PGG improves the efficacy of carboplatin, paclitaxel, and cetuximab chemoimmunotherapy of advanced non-small cell lung cancer (NSCLC).

Imprime PGG is a yeast-derived beta 1,3/1,6 glucan that primes innate immune cells to kill monoclonal antibody (MAb)-targeted cancer cells via a mechanism dependent on complement receptor 3 (CR3). In humans, naturally occurring anti-beta glucan antibodies are required for binding of Imprime PGG to CR3 on immune cells. A quantitative assay has been developed to measure these antibodies in serum; subjects with levels conducive to binding are considered “biomarker positive” (BM+) and others “biomarker negative” (BM-). In a Phase 2 study, stage IIIb or IV NSCLC subjects received cetuximab (250 mg/m2 following initial 400 mg/m2 loading dose) without (Control, N=30) or with Imprime PGG 4mg/kg (Imprime, N=60) on Days 1, 8 and 15 of each 3-week treatment cycle; all subjects also received carboplatin (AUC 6) plus paclitaxel (200 mg/m2) on Day 2 of each cycle for the first 4 to 6 cycles. Maintenance treatment with cetuximab alone or with Imprime was continued in subjects achieving radiographic stable disease or tumor responses (RECIST 1.0). In the efficacy population comprised of all treated subjects who had evaluable baseline and post-baseline scans, median overall survival was 11.2 mo in the control group (N=26), 10.2 mo in the entire Imprime group (N=46) (HR 1.06, p=0.85 vs. control), 16.5 mo in the BM+ Imprime group (N=15) (HR 0.63, p=0.26 vs. control) and 9.1 mo in the BM- Imprime group (N=31) (HR 1.35, p=0.35 vs. control). Three-year survival was 0% in the control group, 7% in the entire Imprime group, 17% in the BM+ Imprime group and 0% in the BM- Imprime group. The objective response rate (ORR, all partial responses) was 23% in the control group, 48% in the entire Imprime group (p= 0.048 vs. control), 67% in the BM+ Imprime group (p=0.009 vs. control) and 39% in the BM- Imprime group (p=0.26 vs. control). Among subjects with squamous cell histology, 6 of 6 BM+ Imprime subjects had responses compared with 3 of 10 control subjects (p=0.01). Grade 3/4 adverse events occurred in 25 of 29 control subjects (86%) and 46 of 59 Imprime subjects (78%). All adverse events were consistent with toxicities attributable to the cytotoxic drugs or cetuximab. In summary, the addition of Imprime PGG to chemoimmunotherapy with carboplatin, paclitaxel and cetuximab resulted in improved outcomes in BM+ subjects with respect to increased ORR and extended survival compared to control subjects and had a good safety profile. Citation Format: Michael Thomas, Parvis Sadjadian, Jens Kollmeier, Zhonglin Hao, Myra Patchen, Jamie Lowe, Paulette Mattson, Richard D. Huhn, Nandita Bose, Mary Antonysamy, Michele Gargano, Keith Gordon, Folker Schneller. Imprime PGG improves the efficacy of carboplatin, paclitaxel, and cetuximab chemoimmunotherapy of advanced non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A26.

1071PCHEMOIMMUNOTHERAPY OF ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC) WITH IMPRIME PGG (IPGG) IN COMBINATION WITH CETUXIMAB, CARBOPLATIN AND PACLITAXEL–ANALYSIS OF SECONDARY ENDPOINTS OF A MULTICENTER, RANDOMIZED PHASE 2 TRIAL

ABSTRACT Aim: IPGG is a yeast-derived b-glucan that primes innate immune cells to kill monoclonal antibody-targeted cancer cells via complement receptor 3 (CR3). Subjects with anti-beta glucan antibodies (ABA) levels conducive to IPGG binding to CR3 are considered “biomarker positive” (BM+). We have previously reported significant improvements in objective responses with IPGG in combination with cetuximab, carboplatin and paclitaxel in patients (pts) with advanced NSCLC. Herein, we present the secondary endpoints of the clinical trial. Methods: Pts with Stage IV NSCLC received cetuximab (CET) 250 mg/m2 following initial 400 mg/m2 loading dose) without (Control, N = 30) or with IPGG 4mg/kg (IPGG, N = 60) on Days 1, 8 and 15 of each 3-week treatment cycle, and carboplatin (AUC 6) + paclitaxel (200 mg/m2) on Day 2 for the first 4 to 6 cycles. Pts achieving radiographic stable disease or tumor response (modified RECIST 1.0) received CET or CET/IPGG maintenance treatment. The primary endpoint was objective response rate. Secondary endpoints included disease control rate (DCR: CR + PR + SD), time to progression (TTP), overall survival (OS) and safety. Results: Best overall response (control vs IPGG) was PR in 23.1% vs 47.8% (p = 0.048), SD in 53.8% vs 30.4%, and PD in 23.1% vs 21.7%, respectively; DCR was 76.9% vs 78.3%, respectively (p = NS). ORR was 66.7% with IPGG in BM+ pts (p = 0.009 vs. Control) and 38.7% in the BM - group (p = NS vs. Control). Median TTP was 4.4 mo vs 4.3 mo respectively in the overall population and 5.6 mo in BM+ pts receiving IPGG (p = NS). OS was 11.3 mo vs 12.4 mo overall (p = NS), and 16.7 mo in BM+ pts vs. 9.4 mo in BM- pts receiving IPGG (p = 0.133). All subjects had at least one adverse event; grade III/IV adverse events occurred in 86.2% vs 78.0% of control vs. IPGG-treated pts. Conclusions: In patients with stage IV NSCLC receiving combination therapy with carboplatin, paclitaxel and CET, IPGG was well tolerated, improved objective responses and prolonged OS in BM+ pts. Disclosure: N. Bose, M.L. Patchen, J. Lowe, P. Mattson, M. Gargano, R.D. Huhn and A. Braun: Employee of Biothera, Inc.All other authors have declared no conflicts of interest.