A phase II, open-label, multicenter study to evaluate the antitumor efficacy of CO-1.01 as second-line therapy for gemcitabine-refractory patients with stage IV pancreatic adenocarcinoma and negative tumor hENT1 expression.

BACKGROUND: Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5'-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. METHODS: Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). RESULTS: Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1-8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. CONCLUSION: This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma.

Genomics and pharmacogenomics of pancreatic adenocarcinoma.

The last decade has brought significant advances in the development of molecularly targeted therapies for treatment of a variety of human malignancies. In contrast to other solid tumors, however, the impact of novel therapeutic strategies on clinical outcomes in patients with pancreas adenocarcinoma (PAC) has been limited to date. Gemcitabine was established as a standard of care for treatment of advanced PAC in 1997 based on an observed improvement in clinical benefit as adjudicated principally by pain scores and analgesic consumption, and demonstration of an overall survival (OS) benefit in a randomized comparison with 5-fluorouracil (5-FU). Since then, multiple agents targeting oncogenic signaling pathways and mediators of angiogenesis have failed to improve outcomes in phase III clinical trials when compared with gemcitabine monotherapy. An exception to this is the anti-epidermal growth factor receptor therapy erlotinib, which yielded a survival benefit in patients with advanced disease in combination with gemcitabine compared with gemcitabine alone, although this was a marginal incremental improvement for which the clinical significant has been heavily debated. More recently, the most significant therapeutic advance in PAC has come from the combination of several cytotoxic agents; infusional 5-FU, irinotecan and oxaliplatin. This combination chemotherapy regimen, known as FOLFIRINOX, improved survival in patients with an excellent functional status and stage IV disease by 4.3 months compared with gemcitabine alone. This improvement in survival did come at the cost expectedly of a significant increase in toxicities, including gastrointestinal and hematologic particularly. Other gemcitabine-based combination chemotherapy regimens including gemcitabine and platinum analogs and gemcitabine and capecitabine have consistently shown an increased response rate but no OS benefit in individual trials; albeit pooled and meta-analyses have indicated a survival benefit in good performance status patient for both these cytotoxic combinations. Accordingly, the 5-year survival for patients with PAC remains <5%, with an annual disease-specific mortality which approaches the incidence. The challenge remains therefore, to develop more effective systemic therapies against this challenging malignancy. Recent progress toward understanding the genetic events in the development of PAC, in combination with advances in the field of pharmacogenomics offer hope that we may build on achievements to-date to develop more effective therapeutic strategies for PAC in years to come.