Threshold Pharmaceuticals, Inc. said, as a result of lack of efficacy and enrolment challenges, it has decided to stop further enrolment and not pursue further clinical investigation ovarian cancer trial, which evaluated two dosing schedules of glufosfamide, a once weekly schedule and a schedule that included glufosfamide every three weeks.
Threshold posted results from a phase II clinical trial of glufosfamide for the treatment of patients with soft tissue sarcoma and from a phase II clinical trial of glufosfamide for the treatment of patients with platinum-resistant ovarian cancer. The company also provided guidance on the clinical development of glufosfamide.
The soft tissue sarcoma trial was completed and 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. In the remaining ongoing clinical trial of glufosfamide, Threshold and its development partner in Japan, MediBIC Co., Ltd, continue to expect to complete an ongoing phase II clinical trial for the treatment of solid tumours in the coming months. The company entered into an agreement with MediBIC in 2004 to develop glufosfamide in Japan and other Asian countries, and a phase I clinical trial commenced in January 2007.
Additionally, Threshold is focused on TH-302, the company's hypoxia-activated prodrug (HAP). TH-302 is a novel cancer therapeutic specifically activated under the low oxygen conditions typical of solid tumour cancer cells and is currently under investigation in a phase I clinical trial in patients with advanced solid tumours.
"While we are disappointed that single-agent glufosfamide does not appear to be an effective treatment option for women with ovarian cancer, the results from the study of soft tissue sarcoma and our previous results from two studies in pancreatic cancer suggest that glufosfamide is an active chemotherapeutic agent for those indications," said Barry Selick, CEO. "That said, with our recent shift in focus to TH-302 and its underlying pipeline of HAP product candidates, we will be seeking a partner with whom to continue development of glufosfamide in these and potentially other indications."
The sarcoma trial evaluated the efficacy and safety of glufosfamide in patients with previously treated, advanced, soft tissue sarcoma. Twenty-two patients with metastatic and/or advanced unresectable soft tissue sarcoma previously treated with one or two prior systemic therapies enrolled in the Phase 2, open-label, clinical trial at various sites in the United States. The primary efficacy endpoint of the trial was the objective response rate. The secondary endpoints of the trial included duration of response, progression-free survival, overall survival and various safety parameters. Tumour response was evaluated at baseline and every six weeks using the Response Evaluation Criteria In Solid Tumours (RECIST). Eight of 18 (44 per cent) evaluable patients demonstrated clinical benefit with a RECIST 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.
Soft tissue sarcoma includes cancers of cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. The American Cancer Society estimated that 9,220 people were diagnosed with a soft tissue sarcoma in the United States in 2007, and approximately 3,560 people died from this disease.
The ovarian cancer clinical trial evaluated two dosing schedules of glufosfamide, a once weekly schedule and a schedule that included glufosfamide every three weeks. All patients were eligible to receive up to six 21-day cycles. Seventeen of the planned 45 subjects have been enrolled and received study drug. The primary efficacy endpoint of the trial was CA-125 response and CA-125 progression free survival. The rate of enrolment in the trial has been problematic. After multiple prior chemotherapies including platinum-containing regimens, otherwise eligible patients did not have adequate renal function for enrolment. In addition, only one confirmed CA-125 response and no confirmed tumour responses have been reported.
Ovarian cancer is the eighth most common cancer among women, and is the fifth most common cause of cancer death among women. The American Cancer Society estimated that 22,430 women were diagnosed with ovarian cancer in the United States in 2007, and approximately 15,280 women died from the disease.