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

Inclusion Criteria Patients must fulfil all of the following criteria.

• Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
• 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)
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
• Histological confirmation of breast cancer with documented positive oestrogen receptor status (ER+) of primary or metastatic tumour tissue according to local laboratory parameters
• Phase IIa: Mandatory provision of tumour biopsy for assessment of oncology biomarkers
• 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
• 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 me