Glufosfamide Clinical Trials

Glufosfamide has been evaluated in one Phase 3, nine Phase 2 and two Phase 1 clinical trials that together enrolled over 500 patients with a variety of advanced-stage cancers. The Company will be seeking a partner to continue development of glufosfamide in cancer.

Recent Clinical Trials

Glufosfamide has been evaluated in pancreatic cancer, small cell lung cancer, ovarian cancer and soft tissue sarcoma.

Pancreatic Cancer

In a Phase 2 clinical trial of glufosfamide in combination with gemcitabine for the treatment of advanced pancreatic cancer, 6 of 28 patients (21%; 95% CI: 8-41%) achieved a partial response including one unconfirmed partial response. Median duration of confirmed responses was 8.4 months. In addition, 11 of 28 patients (39%) experienced stable disease (duration 1.2+ to 12.6+ months). In this clinical trial six-month and one-year survival were 50% (95% CI: 31-67%) and 32% (95% CI: 16 - 49%), respectively. Median progression-free and overall survival were 3.7 and 6.0 months. In the clinical trial, 29 patients were treated, of which 28 patients with pancreatic adenocarcinoma previously untreated with chemotherapy were evaluated for response.

A Phase 3 clinical trial for the second-line treatment of pancreatic cancer did not meet its primary endpoint. While the overall survival in patients in the glufosfamide arm was 18% higher compared to those who received best supportive care (BSC) alone, the result was not statistically significant. The median survival of patients who were treated with glufosfamide was 105 days versus 84 days for the patients who received BSC. In September 2007, data presented at the European Cancer Conference outlined longer overall survival in certain subgroups of patients receiving glufosfamide. A subgroup of diabetic patients taking glucose-lowering agents (primarily sulfonylureas) indicated much improved survival with glufosfamide. The median overall survival of these patients who were treated with glufosfamide (n=7) was 13.7 months (95% CI: 2.8 to NA) versus 2.4 months (95% CI: 1.5 to 3.4) for these patients who received BSC alone (n=14).

Soft Tissue Sarcoma

A Phase 2 clinical trial for the treatment of patients with soft tissue sarcoma provided evidence of clinical activity. The initial analysis of the results supports continued development of the compound for this indication but suggests different dosing regimens would likely be required to improve the therapeutic index. Eight of 18 (44%) evaluable patients demonstrated clinical benefit with an assessment of stable disease or partial response. The most common severe adverse event was renal failure (5 of 22 patients). Renal toxicity was higher than in other glufosfamide studies but several risk factors were identified.

Small Cell Lung Cancer

A Phase 2 clinical trial evaluating the efficacy and safety of glufosfamide in patients with recurrent, sensitive small cell lung cancer has stopped enrollment. The clinical trial utilized a two stage design to ensure there would be an adequate response rate to justify complete enrollment. The first stage enrolled 21 patients as planned, but only one confirmed partial response was observed. If three or more responses were observed, an additional 29 patients would have been enrolled.

Ovarian Cancer

A Phase 2 clinical trial of glufosfamide for the treatment of patients with platinum-resistant ovarian cancer has stopped enrollment due to a lack of efficacy and enrollment challenges. The Company will not pursue further clinical investigation in this indication.

Prior Clinical Trials

In the two Phase 1 trials, escalating doses of glufosfamide were administered to 72 patients with solid tumors not amenable to established treatments. Although Phase 1 trials are designed primarily to assess safety, tumor shrinkage was observed in patients with breast cancer, non-small cell lung cancer, pleural mesothelioma, renal cell carcinoma and cancers of unknown primary origin.

In the Phase 1 trials, the one patient with advanced pancreatic cancer achieved a complete remission, and more than five years after being treated with glufosfamide alone, this patient remained alive and disease-free. This example may not be representative of the activity of glufosfamide when studied in larger trials.

In a Phase 2 trial in chemotherapy naïve patients with advanced pancreatic cancer, two of 34 patients achieved a partial response (defined as 30% or greater tumor diameter shrinkage) and 11 of 34 patients achieved stable disease (defined as less than 30% tumor diameter shrinkage and less than 20% growth in tumor diameter). Overall median survival with glufosfamide was estimated at 5.6 months, and two-year survival was estimated at 9%. The preliminary results of this study, published in the European Journal of Cancer in November 2003, reported a median survival of 5.3 months.

In early Phase 1 and Phase 2 trials, glufosfamide was generally well tolerated, with few drug-related serious adverse events. In particular, glufosfamide’s adverse effects on bone marrow and the kidneys were generally reversible without requiring treatment of the side effects. Only 1% of patients developed severe lowering of the blood platelets, which help to stop bleeding. Toxicity to the kidney, as measured by serum elevation in waste products normally excreted by the kidney, was severe in only 1% of patients. Nausea and vomiting is the most common side effect of glufosfamide treatment.

Potential Increased Selectivity with Fewer Side Effects

Glufosfamide combines the active part of an approved alkylator, a member of a widely used class of chemotherapy drugs, with a glucose molecule. The linkage between glucose and the alkylator is cleaved to release the active drug. With glucose as the side product, glufosfamide has fewer side effects than other drugs in its class, which are known to cause hemorrhagic cystitis, a serious condition characterized by severe bladder bleeding.