Phase 1 of this study will evaluate the maximum tolerated dose (MTD) of XL147 when given in combination with letrozole (Femara) and of XL765 when given in combination with letrozole. After the MTD is established for each combination (Phase 2), subjects will be enrolled to evaluate the preliminary efficacy and safety of these combinations in subjects with breast cancer refractory to a non-steroidal aromatase inhibitor that is ER+/PGR+ and HER2-. Letrozole is used in the treatment of different types of breast cancer, but patients can develop resistance. Upregulation of PI3K activity is one of the most common characteristics of human cancer cells, including breast tumor cells. Activation of PI3K results in stimulation of AKT and mTOR kinases, resulting in the promotion of tumor cell proliferation and survival. Preclinical and retrospective clinical data suggest that aberrant activation of the PI3K pathway may play a role in aromatase inhibitor resistance in patients with ER+, HER2- breast cancer. XL147 is a potent inhibitor of PI3K, and XL765 is a potent dual inhibitor of PI3K and mTOR; therefore either of these compounds in combination with letrozole warrants clinical investigation.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
72
given orally once daily as tablets
given orally twice daily as capsules
given orally once daily as tablets
Investigational Site Number 1537
Los Angeles, California, United States
Investigational Site Number 1601
Denver, Colorado, United States
Investigational Site Number 1238
Fort Meyers, Florida, United States
Investigational Site Number 1441
Chicago, Illinois, United States
Investigational Site Number 1138
Boston, Massachusetts, United States
Investigational Site Number 1331
Ann Arbor, Michigan, United States
Investigational Site Number 1330
Detroit, Michigan, United States
Investigational Site Number 5201
Columbia, Missouri, United States
Investigational Site Number 1252
Durham, North Carolina, United States
Investigational Site Number 1214
Nashville, Tennessee, United States
...and 7 more locations
Safety and tolerability of XL147 and letrozole and XL765 and letrozole
Time frame: at weekly and bi-weekly study visits
In Phase 1, to determine the maximum tolerated dose of XL147 in combination with letrozole and of XL765 in combination with letrozole
Time frame: assessed by weekly study visits
In Phase 2, to evaluate progression-free survival at 3 months
Time frame: tumor assessments at Week 13 and every 8 weeks thereafter
In Phase 2, to assess other clinical benefit and efficacy parameters
Time frame: tumor assessments at Week 13 and every 8 weeks thereafter
Pharmacokinetics and pharmacodynamics of XL147, XL765 and letrozole
Time frame: assessed every 2 weeks, then every 4 weeks
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