E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
recurrent or advanced oestrogen and/or progesterone receptor positive breast cancer |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006198 |
E.1.2 | Term | Breast cancer recurrent |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
1. Efficacy Compare progression-free survival of ATN-224 in combination with exemestane versus exemestane alone, in post-menopausal women with recurrent or advanced, oestrogen and/or progesterone receptor positive breast cancer.
2. Safety Establish the safety of ATN-224 in combination with exemestane in this patient population.
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E.2.2 | Secondary objectives of the trial |
1. Investigate the response rate (overall and at 16 and 24 weeks), response duration, rate of stable disease for ≥16 and ≥24 weeks of patients treated with ATN-224 in combination with exemestane, and of patients treated with exemestane alone 2. Investigate the clinical benefit rate (complete and partial response, stable disease) at 16 and 24 weeks, for patients treated with ATN-224 in combination with exemestane, and for patients treated with exemestane alone. 3. Investigate further the time course of suppression of serum caeruloplasmin (Cp, surrogate for copper) using a 2 week loading dose (300 mg) of ATN-224, followed by 120mg dose for 2 weeks. 4. Investigate serum oestradiol and oestrone sulphate levels in patients treated with ATN-224 with exemestane and in patients treated with exemestane alone (to assess if ATN-224 interacts with the aromatase inhibition of exemestane).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically proven oestrogen and/or progesterone receptor positive breast cancer as defined by at least one of the criteria below:-
Oestrogen Receptor Positivity • a score of 3 or more on a scale (range of 0 to 8), or equivalent score from other grading methods; representing the intensity and percentage of positive-staining tumour cells by immunohistochemistry. • ≥ 5 fmol/mg protein by ligand binding assay or ELISA.
Progesterone Receptor Positivity • a score of 3 or more on a scale (range of 0 to 8) ), or equivalent score from other grading methods; representing the intensity and percentage of positive-staining tumour cells by immunohistochemistry.
2. Patients with recurrent or advanced disease who have received an anti-oestrogen and/or non steroidal aromatase inhibitor as adjuvant treatment or patients who have received an anti-oestrogen or a non-steroidal aromatase inhibitor as first line treatment for advanced disease.
3. Post-menopausal women as defined by one of the following: • surgical or radiation-induced, bilateral oophorectomy at least 1 year in the past; • in women with an intact uterus, no menstrual periods for 12 consecutive months with no other biological or physiological cause; • age 55 years or older;
4. Measurable/evaluable disease as measured by clinical examination, X-ray, computerised tomography (CT) or MRI scan, with at least one lesion that can be followed for response.
5. Life expectancy of at least 6 months.
6. Prior therapy allowed: Adjuvant or neoadjuvant treatment with tamoxifen Adjuvant or neoadjuvant treatment with a non-steroidal aromatase inhibitor Adjuvant/neoadjuvant chemotherapy Tamoxifen or non-steroidal aromatase inhibitor as first line treatment in the metastatic setting
7. Patients with bone metastases only are eligible provided they have at least one lytic lesion (not previously irradiated or planned for irradiation) that can be followed by X-ray or CT scanning. Independent review of X-ray/CT scans will be performed.
8. Patients with cutaneous skin metastases only are eligible provided the skin lesions are > 10 mm and can be followed by good quality photography (ideally performed by medical photography) with a ruler included in the photograph.
9. World Health Organisation (WHO) performance status of 0 to 2
10. 18 years or over.
11. Written (signed and dated) informed consent, and be capable of co-operating with treatment and follow-up.
12. Haematological and biochemical indices within the ranges shown below. These measurements must be performed within one week before the patient starts study treatment. Lab Test Value required Haemoglobin (Hb) ≥9.0 g/dl Neutrophils ≥1.5 x 10(9)/L Platelets ≥100 x 10(9)/L Serum bilirubin ≤1.5 x upper limit of normal (ULN) Alanine amino-transferase (ALT) and/or aspartate amino-transferase (AST) ≤ 2.5 x ULN, unless raised due to tumour in which case up to 5 x ULN is permissible Creatinine clearance ≥50 ml/min (measured or calculated)
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E.4 | Principal exclusion criteria |
1. Radiotherapy (except to control pain or prevent fracture or in the adjuvant setting). Chemotherapy except in the adjuvant setting.
2. Tumours with HER2 over-expression [3+ score as assessed by immunohistochemistry] or HER2 gene amplification [positive result by fluorescence in situ hybridisation (FISH)].
3. Prior treatment with exemestane.
4. Currently receiving treatment with a luteinizing hormone-releasing hormone (LH-RH) analogue.
5. Currently receiving treatment with oral bisphosphonates (i.v. bisphosphonates are permitted).
6. Currently receiving chronic steroid therapy for concurrent illness or cancer. [Short-term steroid use for concurrent illness is allowed, eg for acute asthma].
7. History of malabsorption syndromes or other gastrointestinal disorders that may affect ATN-224 absorption, including bowel obstruction, celiac disease, sprue, cystic fibrosis
8. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ATN-224, omeprazole (or other proton pump inhibitor), or exemestane.
9. Receiving any other copper-binding drug during the study (eg penicillamine or trientine).
10. Use of copper- or zinc-containing vitamins or supplements during the study.
11. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1 toxicities that in the opinion of the Investigator and the Drug Development Office (DDO) should not exclude the patient.
12. Clinically apparent brain metastases.
13. Major thoracic and/or abdominal surgery in the preceding four weeks from which the patient has not recovered.
14. At high medical risk because of non-malignant systemic disease including active uncontrolled infection.
15. Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV).
16. Current malignancies of other types, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal 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 for the study].
17. Concurrent congestive heart failure or prior history of class III/IV cardiac disease (New York Heart Association [NYHA]).
18. Any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial.
19. Is a participant or plans to join in another interventional clinical study, whilst taking part in this Phase II study of ATN-224. Participation in an observational study would be acceptable. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression-free survival of the combination of ATN-224 with exemestane and of exemestane alone.
2. All patients receiving at least one dose of ATN-224 or exemestane will be evaluated for safety by monitoring adverse events, clinical laboratory tests, and physical examinations. Causality of each adverse event to ATN-224 and to exemestane will be determined, and severity graded according to NCI CTCAE Version 3.0. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The 'End of the Trial' is defined as the last visit of the last patient undergoing the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |