Exemestane With or Without ATN-224 in Treating Postmenopausal Women With Recurrent or Advanced Breast Cancer
RATIONALE: Exemestane may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. ATN-224 may stop the growth of breast cancer by blocking blood flow to the tumor. It is not yet known whether giving exemestane together with ATN-224 is more effective than giving exemestane alone in treating patients with recurrent or advanced breast cancer.
PURPOSE: This randomized phase II trial is studying the side effects of exemestane given together with or without ATN-224 and to see how well it works in treating postmenopausal women with recurrent or advanced breast cancer.
Drug: SOD1 inhibitor ATN-224
Genetic: protein expression analysis
Genetic: proteomic profiling
Other: laboratory biomarker analysis
Other: pharmacological study
|Study Design:||Allocation: Randomized
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Cancer Research UK Randomised Phase II Trial of ATN-224 (Copper Binding Agent) in Combination With Exemestane Versus Exemestane Alone in Post-menopausal Women With Recurrent or Advanced, Oestrogen and/or Progesterone Receptor Positive Breast Cancer|
- Progression-free survival
- Response rate (complete and partial response) overall and at 16 and 24 weeks
- Rate of stable disease for ≥ 16 and ≥ 24 weeks
- Response duration
- Clinical benefit rate (complete and partial response, stable disease) at 16 and 24 weeks
- Time (in days) taken after starting SOD1 inhibitor ATN-224 to achieve target serum ceruloplasmin level (5 to 15 mg/dl)
- Levels of serum estradiol and estrone sulphate at day 1 of course 1 and 2
- 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.
- SOD1 activity in red blood cells and cytokine levels in plasma samples
- Circulating endothelial cell and circulating endothelial RNA levels, and proteome profiles in blood samples at baseline and during treatment
- SOD1 and lysyl oxidase expression, and copper-dependent proteins and endothelial growth factor receptor-related cell-signaling pathways in historical tumor samples
|Study Start Date:||June 2008|
|Study Completion Date:||March 2009|
- 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.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00674557
|Cancer Research UK Medical Oncology Unit at Churchill Hospital & Weatherall Institute of Molecular Medicine - Oxford|
|Oxford, England, United Kingdom, OX3 7LJ|
|Principal Investigator:||Adrian L. Harris, MD||Churchill Hospital|