Abstract C287: Efficacy and safety of the TH-302, gemcitabine, and nab-paclitaxel combination in xenograft models of pancreatic cancer

• Published in: Molecular cancer therapeutics 2013-11, Vol.12 (11_Supplement), p.C287-C287
• Main Authors: Sun, Jessica D., Liu, Qian, Ahluwalia, Dharmendra, Li, Wenwu, Wang, Yan, Ruprell, Ayesha S., Hart, Charles P.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-13-C287

Background: Tumors often consist of hypoxic regions which are resistant to chemo- and radiotherapy. TH-302 (T) is an investigational hypoxia-targeted drug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under hypoxic conditions. A randomized Phase 2 clinical trial in pancreatic ductal adenocarcinoma (PDAC) demonstrated a significant increase in progression-free survival from the addition of T to gemcitabine (G) vs. G only (NCT01144455). A Phase 3 trial of G + T compared to G + placebo is currently underway (NCT01746979). G + nab-Paclitaxel (nP) significantly prolonged overall survival in a recent Phase 3 trial (NCT00844649). We investigated the efficacy and safety profile of combining T with G and nP in PDAC xenograft models. Methods: Four PDAC xenograft models were established by s.c. implantation of Hs766t, MIA PaCa-2, PANC-1 and BxPC-3 cells into the flank of nude mice. A ‘same day’ administration of T, nP and G with a Q3Dx5 regimen was employed: T, 50mg/kg, ip; nP: 30mg/kg, iv; and G: 60mg/kg ip. Saline treated animals served as vehicle control (V). Antitumor activity of the G + nP + T triplet was assessed, and compared with the G + nP doublet. Hematological, blood chemistry, and immunohistochemical-based analyses were also performed in PANC-1 bearing nude and/or CD-1 mice. Samples were collected 24 hours after the last treatment. Neuropathy assays were performed in CD-1 mice. Results: Using tumor growth inhibition, and Kaplan-Meier analysis of median time to tumor size of 1000mm3 to evaluate antitumor activity, G + nP + T triplet exhibited enhanced efficacy compared with T-alone or the G + nP in all four models. Of note, the complete response rate (CR) of G + nP + T in the PANC-1 model reached 100%, compared to 10% and 50% in the T-alone and G + nP, respectively. G + nP or T-alone treatment reduced neutrophils or lymphocytes compared with V, but there was no additional decrease in neutrophil or lymphocyte count when T was added to G + nP compared to G + nP. Plasma ALT and AST levels were elevated after G + nP treatment, and G + nP + T did not further increase the levels of these liver function parameters. By immunostaining, Ki67-positive cells (a marker of cell proliferation) were significantly reduced after the drug treatment in the PANC-1 xenograft, and to a greater magnitude in G + nP + T. The necrotic region in G + nP + T was increased compared with all other groups. Employing the von Frey neuropathy assay, G + nP tre