NCT00674557TerminatedPhase 2
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
Conditions
Drugs
Trial Snapshot
- Phase
- Phase 2
- Status
- Terminated
- Sponsor
- Cancer Research UK
- Enrollment
- 111
- Locations
- 2
- Primary Endpoint
- Progression-free survival
Study Overview
Brief Summary
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.
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •DISEASE CHARACTERISTICS:
- •Histologically confirmed breast cancer
- •Recurrent disease after 2-3 years of adjuvant treatment with an anti-estrogen (documented by imaging techniques)
- •Advanced disease that has recurred during or after anti-estrogen therapy
- •Measurable or evaluable disease by conventional techniques, with ≥ 1 lesion that can be followed for response
- •Bone metastases only are eligible provided they have ≥ 1 lytic lesion (not previously irradiated or planned for irradiation) that can be followed by X-ray or CT scanning
- •Cutaneous skin metastases only are eligible provided the skin lesions are > 10 mm and can be followed by good quality photography with a ruler included in the photograph
- •No clinically apparent brain metastases
- •Hormone receptor status must meet 1 of the following criteria:
- •Estrogen receptor-positivity
- •Score ≥ 3 on a scale (range of 0 to 8), or equivalent score from other grading methods, representing the intensity and percentage of positive-staining tumor cells by immunohistochemistry
- •Greater than or equal to 5 fmol/mg protein by ligand binding assay or ELISA
- •Progesterone receptor-positivity
- •Score ≥ 3 on a scale (range of 0 to 8) or equivalent score from other grading methods, representing the intensity and percentage of positive-staining tumor cells by immunohistochemistry
- •No HER-2 overexpression, defined as gene amplification by fluorescence in situ hybridization [FISH] OR 3+ overexpression by IHC)
- •PATIENT CHARACTERISTICS:
- •Postmenopausal as defined by any of the following:
- •Surgical or radiation-induced
- •No menstrual periods for 12 consecutive months with no other biological or physiological cause in women with an intact uterus
- •Age ≥ 55 years
- •WHO performance status 0-2
- •Life expectancy ≥ 6 months
- •Hemoglobin ≥ 9.0 g/dL
- •ANC ≥ 1.5 x 10^9/L
- •Platelet count ≥100 x 10^9/L
- •Serum bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •ALT and/or AST ≤ 2.5 times ULN (5 times ULN if due to tumor)
- •Creatinine clearance ≥ 50 mL/min
- •No history of malabsorption syndromes or other gastrointestinal disorders that may affect SOD1 inhibitor ATN-224 absorption, including any of the following:
- •Bowel obstruction
- •Celiac disease
- •Cystic fibrosis
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to SOD1 inhibitor ATN-224, omeprazole (or other proton pump inhibitor), or exemestane
- •No non-malignant systemic disease including active uncontrolled infection
- •No serologic positivity for hepatitis B, hepatitis C, or HIV
- •No concurrent congestive heart failure
- •No history of NYHA class III-IV cardiac disease
- •No other concurrent malignancy, except adequately treated cone-biopsied carcinoma in situ of the uterine cervix, basal cell or squamous cell carcinoma of the skin
- •Cancer survivors who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for 5 years, and are deemed at low risk for recurrence are eligible
- •No other condition which, in the investigator's opinion, would not make the patient a good candidate for this study
- •PRIOR CONCURRENT THERAPY:
- •See Disease Characteristics
- •Recovered from all prior therapy (alopecia allowed)
- •At least 1 year since prior bilateral oophorectomy
- •Prior adjuvant or neoadjuvant treatment with tamoxifen allowed
- •Prior adjuvant therapy with a non-steroidal aromatase inhibitor allowed
- •More than 4 weeks since prior immunotherapy or chemotherapy (6 weeks for nitrosoureas and mitomycin-C)
- •More than 4 weeks since prior major thoracic and/or abdominal surgery
- •More than 3 weeks since prior endocrine therapy
- •More than 4 weeks since prior and no concurrent radiotherapy (except to control pain or prevent fracture)
- +9 more not shown
Exclusion Criteria
- Not provided
Outcomes
Primary Outcomes
Progression-free survival
Safety
Secondary Outcomes
- 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
Investigators
Study Sites (2)
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