Diez, Pedro M. Quintana

Abstract Abstract 4723 Introduction: Combination G/A has been shown to be apromising investigational therapy for patients with metastatic pancreatic cancer. A randomized phase II trial was initiated to determine if ODSH, a low anticoagulant heparin derivative that blocks several pancreatic cancer cell survival pathways, would enhance the efficacy of G/A. Preliminary data from the first 10 patients administered ODSH demonstrated an unexpected and profound preservation of peripheral blood counts, despite the highly myelosuppressive G/A regimen they also received. Methods: Patients with previously untreated, metastatic pancreatic cancer were treated with G (1000 mg/m2) and A (125 mg/m2) on days 1, 8, and 15 every 28 days until either disease progression or unacceptable toxicities ensued. ODSH (4 mg/kg bolus followed by a 48 hr. continuous IV infusion at a dose of 0.375 mg/kg/hr for 48 hrs) was administered with each treatment. The first 10 patients received A/G plusODSH with plans for a randomized comparison between A/G with and without ODSH involving 50 patients. Patients were required to have ECOG 0–1 as well as adequate hematological and bilirubin level <1.5 ULN. G-CSF administration was permitted per investigator discretion. Here we present hematological data on the 10 patients treated with A/G plus ODSH. Results: 10 patients were administered up to 5 cycles of G/A plus ODSH. The patients had a median age of 66 years (range, 59 to 75 years) and 50% were male. The median platelet and neutrophil counts prior to each cycle are listed in Table 1. No patients had grade 3/4 thrombocytopenia during any of the cycles. Forty percent of patients had grade 3 neutropenia, but none had grade 4 during any of the cycles. Only 1 patient received 1 dose of G-CSF after day 15 in cycle #1. Conclusions: A previous trial of G/A in patients with previously untreated, metastatic pancreatic cancer reported grade 3/4 thrombocytopenia and neutropenia in 28% (19% grade 3 and 9% grade 4) and 75% (26% grade 3 and 49% grade 4) of patients, respectively (Von Hoff, J Clin Oncol, 2011). With the addition of ODSH to an equivalent chemotherapy regimen in a similar patient cohort, the current trial reported grade 3 thrombocytopenia and neutropenia in 0% and 40% of patients, respectively, with no patients having grade 4 thrombocytopenia or neutropenia. With successive cycles, median platelet counts were stable to improved and a trend existed for reduced neutropenia with ODSH treatment. An explanation for the apparent salutary effects of ODSH on marrow function may involve its interaction with platelet factor 4 (PF4). PF4 is released from the alpha-granules of injured megakaryocytes after chemotherapy delivery. Increased PF4 levels promote thrombocytopenia by inhibiting thrombopoietin production and megakaryopoiesis (Lambert, Blood, 2007; Lambert, Int J Radiation Oncology Biol Phys, 2011). The high molecular weight and strong negative charge of ODSH may result in avid binding to platelet factor 4 (PF4), possibly leading to decreased PF4 levels and more rapid post-chemotherapy platelet recovery (Joglekar, Thromb Haemost, 2012). PF4 may also facilitate neutrophil adhesion to endothelial cells, and reduced PF4 levels from ODSH binding may demarginate and preserve neutrophil values (Kasper, Blood, 2006). Further study of ODSH as a marrow protective agent in myelosuppressivechemotherapy regimens is warranted. Disclosures: Off Label Use: The use of nab-paclitaxel and ODSH in pancreatic cancer. Marcus:Paringenix: Employment, Equity Ownership. Quintana Diez:Paringenix, Inc.: Employment.

284 Background: ODSH, a low anticoagulant heparin derivative, interferes with several important pancreatic cancer cell survival pathways. A randomized phase II trial was initiated to determine if ODSH improves the activity of G/A, a promising pancreatic cancer investigational therapy. Preliminary data are presented here for the first 10 patients administered ODSH as part of an initial run-in phase prior to patient randomization. Methods: Patients with previously untreated, metastatic pancreatic cancer were treated with G (1,000 mg/m2) and A (125 mg/m2) plus ODSH (4 mg/kg bolus followed by a 48 hr. continuous IV infusion at a dose of 0.375 mg/kg/hr) on days 1, 8, and 15 every 28 days until disease progression or unacceptable toxicity. Patients were required to have ECOG ≤ 1 and appropriate blood and liver function levels. The primary endpoint was progression-free survival (PFS). Results: 10 patients (median age, 66 years) were administered up to 5 cycles of G/A plus ODSH. Per RECIST criteria, a partial response (PR) was achieved in 5 patients (50%) and the median PFS will exceed 6 months. Disease control (PR or stable disease for > 16 weeks) occurred in all 10 patients. Of 9 patients with baseline elevated CA 19-9 levels, 8 had > 60% reduction. ODSH was well tolerated and unexpectedly appeared to preserve marrow function as no patients had grade 3/4 thrombocytopenia or grade 4 neutropenia during any of the cycles. Conclusions: Although G/A and FOLFIRINOX are important advances, additional progress is necessary for metastatic pancreatic cancer patients. ODSH may interfere with pancreatic cancer invasion, metastasis, and chemo-resistance by inhibiting P- and L-selectins, heparanase, and the HMGB1-RAGE axis, respectively, suggesting that ODSH may enhance chemotherapy activity. This preliminary analysis in a small number of patients is encouraging and consistent with a previous report for this regimen (Von Hoff, J Clin Oncol, 2011). ODSH has also been very well tolerated and early data suggests that it may preserve platelet and neutrophil levels. Further follow-up of the ongoing randomized phase II trial is warranted. Clinical trial information: NCT01461915.