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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


Phase 2
18 Years
N/A
Not Enrolling
Female
Breast Cancer

Thank you

Trial Information

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


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.

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

- Sprue

- 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)

- No prior exemestane

- Concurrent iron-containing vitamins or supplements are allowed

- No concurrent luteinizing hormone-releasing hormone analog

- No concurrent oral bisphosphonates (IV bisphosphonates allowed)

- No concurrent chronic steroid therapy for concurrent illness or cancer (short-term
steroid use for concurrent illness allowed [e.g., for acute asthma])

- No concurrent copper- or zinc-containing vitamins or supplements

- No concurrent participation in another interventional clinical study (participation
in an observational study allowed)

- No other concurrent copper-binding drug (e.g., penicillamine or trientine)

- No other concurrent anticancer therapy or investigational agent

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Safety Issue:

No

Principal Investigator

Adrian L. Harris, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Churchill Hospital

Authority:

United States: Federal Government

Study ID:

CDR0000595074

NCT ID:

NCT00674557

Start Date:

June 2008

Completion Date:

Related Keywords:

  • Breast Cancer
  • recurrent breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • stage IV breast cancer
  • HER2-negative breast cancer
  • estrogen receptor-positive breast cancer
  • progesterone receptor-positive breast cancer
  • Breast Neoplasms

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