Exelixis reports updated interim data from trials of XL765 small molecule inhibitor of PI3K and mTOR

Exelixis, Inc.Jun 7 2010

Exelixis, Inc. (Nasdaq: EXEL) today reported updated interim data from three ongoing trials of XL765 (SAR245409), an orally available small molecule inhibitor of phosphoinositide-3-kinase (PI3K) and mTOR. 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 XL765 with sanofi-aventis.

"XL765 has unique clinical potential because it inhibits the signaling of both PI3K and mTOR, two important nodes in this critical pathway," said Michael M. Morrissey, Ph.D., president of research and development at Exelixis. "PI3K signaling is dysregulated in a broad spectrum of human cancers, and mTOR is a well validated target for cancer therapy. The results from these studies suggest that this novel compound may have clinical activity as a single agent and in combination with targeted agents and chemotherapy. These data support the ongoing broad phase 1/2 clinical program and further phase 2 evaluation that sanofi-aventis and Exelixis have planned for XL765."

XL765 in Patients with Advanced Malignancies

Interim results from an ongoing phase 1 dose-escalation trial of XL765 in patients with advanced malignancies (Abstract #3030) will be presented in a poster discussion session on Sunday, June 6 by Dr. Irene Brana from Vall d'Hebron University Hospital in Barcelona, Spain. The study is evaluating the safety, tolerability, and clinical activity of continuous daily dosing of XL765 administered once daily (qd) or twice daily (bid). As of May 3, 2010, 83 patients have been enrolled (31 qd and 52 bid). The maximum tolerated doses (MTDs) for qd and bid administration are 90 mg and 50 mg, respectively.

Twelve patients had been on treatment for ≥16 weeks with 7 patients remaining on treatment for ≥24 weeks. XL765 administered qd or bid was generally well tolerated. Most adverse events (AEs) were grade 1 or 2 in severity. The most frequent treatment-related grade 3 AEs were liver function test elevations which were asymptomatic and reversible. Pharmacodynamic (PD) analyses provide evidence of robust PI3K pathway inhibition, which was similar between the qd and bid regimens. Reductions in both PI3K and ERK pathway signaling in tumors were observed.

XL765 Combined with Erlotinib in Patients with NSCLC

Interim results from an ongoing phase 1b/2 study of XL765 in combination with erlotinib in patients with advanced solid tumors (Abstract #3015) will be presented in a poster session on Sunday, June 6 by Dr. Roger Cohen from Fox Chase Cancer Center in Philadelphia, PA. The study is evaluating the safety, tolerability, and clinical activity of escalating doses of XL765 in combination with daily erlotinib at 100 or 150 mg qd, with both drugs administered daily in a 28-day cycle. As of May 3, 2010, 28 patients with advanced solid tumors have been treated with XL765, on both the qd and bid regimens, across 6 dose cohorts in combination with 100 mg erlotinib.

Four non-small cell lung cancer (NSCLC) patients have been on study for ≥16 weeks. The maximum tolerated doses have not been determined in either the qd or bid regimen. The majority of AEs were grade 1 or 2 in severity. One patient had a dose-limiting toxicity (DLT) of grade 3 rash. PK analyses indicate that there are no major interactions between XL765 and erlotinib. PD analyses indicate robust inhibition of PI3K and EGFR pathway signaling in surrogate and tumor tissues.

XL765 Combined with Temozolomide in Patients with Glioblastoma

Interim results from an ongoing phase 1b/2 study of XL765 in combination with temozolomide (TMZ) in patients with newly diagnosed malignant glioma (Abstract #3085) will be presented in a poster session on Monday, June 7 by Dr. Leia Nghiemphu from UCLA School of Medicine in Los Angeles, CA. The study is evaluating the safety, tolerability, and clinical activity of escalating doses of XL765 administered daily in a 28-day cycle in combination with TMZ at 200 mg/m²/day on Days 1-5 of the cycle. Patients must be on a maintenance dose of TMZ at 200 mg/m²/day for at least one cycle prior to enrollment. As of May 3, 2010, 22 patients have been treated with XL765, in both qd and bid regimens, across 5 dose cohorts in combination with TMZ.

Eleven patients have remained on treatment for at least 16 weeks, including 1 patient with a PTEN mutation and EGFR gene amplification who remained on treatment for 62 weeks (a total of 97 weeks following chemoradiation). The maximum tolerated dose has not been established for either the qd or bid regimen. Most AEs were grade 1 or 2 in severity. DLT occurred in 2 patients: 1 patient had grade 3 brain edema and grade 4 thrombocytopenia and 1 patient had a grade 3 rash. Preliminary PK analyses indicate that the PK profiles of XL765 and TMZ administered in combination are similar to the profiles of each compound administered as a single agent. Pharmacodynamic assessments in serial skin biopsies show evidence of PI3K inhibition similar to that observed in the single agent phase 1 study in patients with advanced malignancies.

To access the abstracts and clinical data posters mentioned in this press release, please visit www.exelixis.com.