Methods: Pts with glioblastoma or anaplastic/mixed gliomas receive TMZ 200 mg/m2/day on Days 1–5, and XL765 qd in 28‐day cycles. Pts must be on a maintenance TMZ dose of 200 mg/m2/day for at least one 28‐day cycle prior to enrollment. Cycle 1 safety data determine dose‐limiting toxicities (DLTs). Tumor response is assessed by the modified Macdonald criteria every 8 weeks.

Results: As of 24Aug2009, 15 pts (12 with glioblastoma, 2 with mixed glioma and 1 diagnosed with anaplastic oligodendroglioma) have been treated with XL765 in combination with TMZ across 3 dose levels of XL765 (30, 40, and 60 mg qd). The MAD has been identified as 60 mg for the once‐daily schedule. Two of 6 pts at the 60 mg XL765 dose level experienced DLTs: one pt experienced DLTs of Grade 3 brain edema and Grade 4 thrombocytopenia (these events were also reported as related SAEs) and the other pt experienced a DLT of Grade 3 diffuse maculopapular rash. Three additional pts experienced SAEs that were not attributed to study treatment. With the exception of the DLTs described above, all AEs reported for 12 pts (as of 03Aug2009) were Grade 1 or Grade 2. Preliminary data suggest no PK interaction between XL765 and TMZ. XL765 PK when given in combination with TMZ are consistent with the PK of single‐agent XL765 (Exelixis study XL765‐001), and TMZ exposure in this study is similar to that published for single‐agent TMZ. At the 30 and 40 mg qd XL765 dose levels, inhibition of PI3K pathway signaling has been demonstrated in paired skin biopsies using immunofluorescent analysis of pAKT‐T308, pAKT‐S473, and p4EBP1. Based on an initial molecular assessment of archival tumor material the most common molecular alterations detected included MGMT promoter methylation (5 of 12 evaluated pts), PTEN point mutations (8 of 14 evaluated pts), and EGFR gene amplification (7 of 11 evaluated pts). Of the first 12 pts that were enrolled, six pts have remained on study for at least 16 weeks, one of whom continues on study for 50+ weeks (a total of 78+ weeks following chemoradiation). Archival tumor tissue from this pt exhibited MGMT promoter methylation, PTEN mutation, and EGFR amplification.

Conclusions: XL765 in combination with TMZ is generally well tolerated at doses up to 40 mg qd. No apparent PK interaction between XL765 and TMZ has been observed.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B265.