AZD4547 & Anastrozole or Letrozole (NSAIs) in ER+ Breast Cancer Patients Who Have Progressed on NSAIs (RADICAL)

1. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up

2. Aged ≥ 25 years of age (N.B. in line with other studies with AZD4574 and due to concerns of possible effects on the immature skeleton)

3. Post menopausal women. Women will be considered postmenopausal if they have had a bilateral oophorectomy or the following specific requirements apply:

Safety run-in:

* Women under 50 years old would be considered post-menopausal if they have been amenorrhoeic for 24 months and have follicle-stimulating hormone (FSH) and oestradiol levels in the post-menopausal range. Patients with prior exposure to depot Luteininzing hormone releasing hormones (LHRH) analogues must be 24 months or more following the last administration

* Women aged 50 years and older would be considered post-menopausal if they have been amenorrhoeic for 12 months and patients with prior exposure to depot LHRH analogues must be 12 months or more following the last administration

* Women rendered amenorrhoeic by adjuvant chemotherapy, who were premenopausal or perimenopausal prior to chemotherapy, must have been amenorrhoeic for at least 24 months

Phase IIa:

* Women under 50 years old would be considered post-menopausal if they have been amenorrhoeic for 24 months and have follicle-stimulating hormone (FSH) and oestradiol levels in the post-menopausal range.

* Women aged 50 years and older would be considered post-menopausal if they have been amenorrhoeic for 12 months

* Women rendered amenorrhoeic by adjuvant chemotherapy, who were premenopausal or perimenopausal prior to chemotherapy, must have been amenorrhoeic for at least 24 months

* Perimenopausal women rendered amenorrhoeic from exposure to depot LHRH analogues\*

* Patients must have taken LHRH analogues for at least 6 months

4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks

5. Histological confirmation of breast cancer with documented positive oestrogen receptor status (ER+) of primary or metastatic tumour tissue according to local laboratory parameters

6. Phase IIa: Mandatory provision of tumour biopsy for assessment of oncology biomarkers

7. Fulfils criteria for previous treatment of breast cancer\*:

Safety run-in:

* Relapse during a single regimen of adjuvant endocrine therapy with either anastrozole or letrozole or

* Progression during first line endocrine therapy with a non-steroidal Aromatase Inhibitor (AI) for advanced breast cancer\*\*. Co-administration of a targeted agent with the non-steroidal AI is permitted providing all toxicities have recovered to CTCAE Grade 1 or below 1 prior regimen of chemotherapy in the advanced setting is permitted. Chemotherapy administered in the adjuvant setting is permitted

Phase IIa:

o Progressing or progression at some point during breast cancer treatment on endocrine therapy with a non-steroidal AI.\*\*\* Co-administration of a targeted agent with the non-steroidal AI is permitted providing all toxicities have recovered to CTCAE Grade 1 or below.

* Prior chemotherapy in the advanced and adjuvant setting is permitted.

* Prior treatment with exemestane with or without everolimus is permitted.

* Human Epidermal Growth Factor Receptor 2 (HER2) positive breast cancer patients should have been offered at least one prior line of HER2 directed therapy \*\*Advanced breast cancer: metastatic disease or locally advanced disease which is not amenable to treatment with curative intent \*\*\*anastrozole or letrozole does not have to be the most recent therapy

8. Safety run-in: At least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI/plain x-ray at baseline and follow up visits Phase IIa: At least one lesion ≥ 10mm in the longest diameter at baseline (or ≥ 15mm in the short axis for nodal disease) that can be accurately measured with CT/MRI at baseline and is suitable for accurate repeated measurements. Patients with bone only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can be accurately assessed by CT or MRI.

9. Safety run-in: Study entry must be preceded by a minimum of 21 days of anastrozole or letrozole treatment Phase IIa: No set duration of anastrozole or letrozole treatment prior to study entry.

What this study is about