Interim data from multiple ongoing trials of XL147 PI3K inhibitor to be presented at ASCO 2010

Exelixis, Inc. (Nasdaq:EXEL) today reported updated interim data from three ongoing trials of XL147 (SAR245408), a selective, orally available small molecule inhibitor of phosphoinositide-3-kinase (PI3K). Activation of the PI3K pathway is a frequent event in human tumors, promoting cell proliferation, survival, and resistance to chemotherapy and radiotherapy. The pathway also has been implicated as a mediator of resistance to agents targeting epidermal growth factor receptor (EGFR) family members. The presentations will be made at the 2010 Annual Meeting of the American Society of Clinical Oncology, which is being held June 4-8 in Chicago. Exelixis is developing XL147 with sanofi-aventis.

"XL147 is the leading class I selective PI3K inhibitor and has significant clinical and commercial potential in a variety of cancer indications," said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. "The results of the studies being presented at ASCO continue to highlight the potential utility of XL147 as a single agent or in combination with other therapies that are mainstays of cancer treatment. These data provide the foundation for the broad phase 2 program that is currently underway for XL147, including new trials in metastatic breast and endometrial cancers."

XL147 in Patients with Advanced Malignancies

Interim results from an ongoing phase 1 dose-escalation trial of XL147 in patients with advanced malignancies (Abstract #3004) will be presented in a Clinical Science Symposium at 8:30 am on Monday, June 7 by Dr. Gerald Edelman from the Mary Crowley Medical Research Center in Dallas, TX. Patients are treated once daily on either an intermittent schedule (21 days on/7 days off; 21/7) or a continuous daily dosing schedule (CDD). Both a capsule and a tablet formulation are being evaluated. As of April 1, 2010, 78 patients with advanced solid tumors have been enrolled. The maximum tolerated doses (MTDs) for both the 21/7 and CDD schedules with the capsule formulation are 600 mg. The MTD for the tablet formulation has not been determined. Enrollment of lymphoma patients has been initiated.

Seventy-five patients were evaluable for antitumor activity. Of these, 14 have been on treatment ≥16 weeks, including 10 on treatment ≥24 weeks and 4 on treatment ≥40 weeks. One patient with non-small cell lung cancer (NSCLC) who had received 4 prior treatment regimens had a partial response (PR) after 56 weeks on study. Safety data were available for 62 patients. Most adverse events (AEs) were grade 1 or 2 in severity. Dose-limiting toxicities (DLTs) were skin rash and hypersensitivity. Pharmacokinetic (PK) analyses indicate that exposure increased dose-proportionally from 30 to 400 mg with the capsule formulation, and that exposures were similar for the 400 mg, 600 mg, and 900 mg doses. Mean half-life was 5 days. Pharmacodynamic (PD) analyses indicate robust inhibition of PI3K and ERK pathway signaling.

XL147 Combined with Carboplatin and Paclitaxel in Patients with Advanced Solid Tumors

Interim results from an ongoing phase 1b/2 study of XL147 in combination with carboplatin and paclitaxel in patients with advanced solid tumors (Abstract #3078) will be presented in a poster session on Monday, June 7 by Dr. Anne Traynor from the University of Wisconsin Carbone Cancer Center in Madison, WI. The study is evaluating the safety, tolerability, and clinical activity of escalating doses of XL147 administered daily in combination with paclitaxel and carboplatin administered intravenously on Day 1 of each 21-day cycle. In Part A of the study, paclitaxel and carboplatin have been dose-escalated to 175 mg/m² and AUC 6, respectively. As of March 31, 2010, 24 patients have been enrolled and treated using an XL147 capsule formulation. MTD determination using an XL147 tablet formulation has recently been initiated. Cohorts of patients with endometrial cancer and ovarian cancer will be enrolled at the MTD. In Part B, paclitaxel and carboplatin will be dose-escalated up to 225 mg/m² and AUC 6, respectively, with expansion at the MTD in patients with NSCLC.

Twenty two patients were evaluable for tumor response. One patient has experienced a confirmed complete response (CR) and 4 have had confirmed PRs. All responses occurred in patients who were previously treated with a platinum-containing regimen. Fourteen of the 22 evaluable patients remained on treatment ≥12 weeks, with 5 patients on treatment ≥24 weeks. In addition, a platinum-naïve patient with triple-negative inflammatory breast cancer experienced regression of cutaneous lesions after 2 cycles. Safety data were available for 19 patients. Most AEs were grade 1 or 2 in severity. Three DLTs have been reported: 2 patients with a history of drug allergies experienced grade 3 allergic reactions, which resolved after discontinuation of study treatment, and 1 patient experienced grade 3 rash without symptoms of allergic reaction, which resolved following XL147 interruption. PK analyses indicate that there are no major interactions between XL147, paclitaxel, and carboplatin. PD analyses of matched tumor biopsies provide evidence for inhibition of PI3K pathway signaling.

XL147 Combined with Erlotinib in Patients with Advanced Solid Tumors

Interim results from an ongoing phase 1b/2 study of XL147 in combination with erlotinib in patients with advanced solid tumors (Abstract #3070) will be presented in a poster session on Monday, June 7 by Dr. Cristian Moldovan from Institut Goustave Roussy in Villejuif, France. The study is evaluating the safety, tolerability, and clinical activity of escalating doses of XL147 administered daily for 21 days of a 28-day cycle, in combination with erlotinib administered daily. As of April 1, 2010, 28 patients with advanced solid tumors had been enrolled in the trial and treated at 7 dose levels up to 600 mg XL147/150 mg erlotinib. The preliminary MTD is 400 mg XL147/150 mg erlotinib.

Twenty-six patients were evaluable for tumor response. One patient with NSCLC who had prior chemotherapy but was erlotinib naïve achieved a PR and a 59% decrease of metastatic disease after Cycle 3, with a 24-week duration of response. Seven additional patients had SD ≥8 weeks, 4 of which remained on treatment for ≥24 weeks. Safety data were available for 22 patients. Most AEs were grade 1 or 2 in severity. One patient had a DLT of drug rash with eosinophilia and systemic symptoms (DRESS syndrome) at 600 mg XL147/150 mg erlotinib. The patient subsequently died from progressive disease and DRESS. PK analyses indicate that there are no major interactions between XL147 and erlotinib. PD analyses indicate robust inhibition of PI3K and EGFR pathway signaling in surrogate and tumor tissues.