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

Inclusion Criteria

• •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.