Primary Outcome Measures:
- Progression-free survival [ Designated as safety issue: No ]
- Safety [ Designated as safety issue: Yes ]
Secondary Outcome Measures:
- Response rate (complete and partial
response) overall and at 16 and 24
weeks [ Designated as safety issue: No ]
- Rate of stable disease for ≥ 16 and
≥ 24 weeks [ Designated as safety issue: No ]
- Response duration [ Designated as safety issue: No ]
- Clinical benefit rate (complete and partial
response, stable disease) at 16 and 24
weeks [ Designated as safety issue: No ]
- Time (in days) taken after starting SOD1 inhibitor ATN-224
to achieve target serum ceruloplasmin level (5 to 15
mg/dl) [ Designated as safety issue: No ]
- Levels of serum estradiol and estrone
sulphate at day 1 of course 1 and 2 [ Designated as safety issue: No ]
- Molybdenum levels at single time-points at
the beginning of course 1 to 6 in patients
taking SOD1 inhibitor ATN-224 in combination with
exemestane. [ Designated as safety issue: No ]
- SOD1 activity in red blood cells and
cytokine levels in plasma samples [ Designated as safety issue: No ]
- Circulating endothelial cell and circulating
endothelial RNA levels, and proteome
profiles in blood samples at baseline and
during treatment [ Designated as safety issue: No ]
- SOD1 and lysyl oxidase expression, and
copper-dependent proteins and endothelial growth factor receptor-related
cell-signaling pathways in
historical tumor samples [ Designated as safety issue: No ]
OBJECTIVES:
Primary
- Compare progression-free survival of postmenopausal women with, estrogen receptor- and/or progesterone receptor-positive recurrent or advanced breast cancer treated with exemestane with versus without SOD1 inhibitor ATN-224.
- Establish the safety of SOD1 inhibitor ATN-224 in combination with exemestane in these patients.
Secondary
- Determine the response rate (overall, at 16 and 24 weeks), response duration, and rate of stable disease for ≥ 16 and ≥ 24 weeks in these patients.
- Determine the clinical benefit rate (complete response, partial response, and stable disease) at 16 and 24 weeks in these patients.
- Investigate the time course of suppression of serum ceruloplasmin (Cp, surrogate for copper).
- Investigate serum estradiol and estrone sulphate levels in these patients to assess if SOD1 inhibitor ATN-224 interacts with the aromatase inhibition of exemestane.
Tertiary
- Investigate the pharmacokinetic behavior of SOD1 inhibitor ATN-224 in combination with exemestane.
- Investigate superoxide dismutase 1 (SOD1) activity in red blood cells and cytokine levels in plasma samples from these patients.
- Investigate circulating endothelial cell levels, circulating endothelial RNA levels, and proteome profiles in blood samples at baseline and during treatment, from these patients.
- Investigate SOD1, lysyl oxidase and copper-dependent proteins expression, and endothelial growth factor receptor-related cell-signaling pathways in historical tumor samples from all patients entered on the study.
OUTLINE: This is a multicenter study. Patients are stratified according to prior aromatase inhibitor therapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive oral exemestane and oral SOD1 inhibitor ATN-224 once daily.
- Arm II: Patients receive oral exemestane once daily. In both arms, treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically for pharmacokinetic and pharmacodynamic assessments, including Cp levels, estradiol and estrone sulfate, SOD1 levels, cytokines, proteomics, circulating endothelial RNA, circulating endothelial cells, protein expression, and EGFR-related cell signaling pathways.
After completion of study treatment patients are followed at 28 days.