Inclusion Criteria:
1. Signed written informed consent.
2. \>= 18 years
3. Any menopausal status:
1. Pre-menopausal women must have commenced treatment with an LHRH agonist at least 4 weeks prior to starting AZD9833 (± combination IMP(s)) and must be willing to continue to receive LHRH agonist therapy for the duration of the study
2. Post-menopausal defined according to standard criteria in the protocol.
4. Histological or cytological confirmation of adenocarcinoma of the breast
5. Documented positive oestrogen receptor status of primary or metastatic tumour tissue, according to the local laboratory parameters.HER-2 negative.
6. Metastatic disease or locoregionally recurrent disease which is refractory or intolerant to existing therapy(ies) known to provide clinical benefit
7. Metastatic or locoregionally recurrent disease and radiological or objective evidence of progression on or after the last systemic therapy prior to starting IMP
8. Prior chemotherapy, endocrine therapy and other therapy as follows:
1. No more than 2 lines of chemotherapy for advanced disease
2. Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting
3. There is no limit on the number of lines of prior endocrine therapies
4. Prior treatment with CDK4/6 inhibitors is permitted
9. Women of childbearing potential must agree to use a highly effective contraceptive measure, must not be breast feeding, and must have a negative pregnancy test prior to the start of dosing.
10. At least one lesion (measurable and/or non-measurable, as per RECIST 1.1 that can be accurately assessed at baseline and is suitable for repeated assessment by CT, MRI, or plain X-ray; or clinical examination. Blastic-only lesions in bone are not considered assessable.
11. ECOG/ WHO performance status 0 to 1, with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks Inclusion criteria for the paired tumour biopsy research:
Inclusion criteria for the paired tumour biopsy research
12. Disease suitable for paired baseline and on-study tumour biopsies
13. Washout from prior fulvestrant: 6 months
14. Washout from prior tamoxifen: 4 months
15. Signed written informed consent for tumour biopsies
Exclusion Criteria
1. Intervention with any of the following
1. Any cytotoxic chemotherapy, investigational agents/other anti-cancer drugs for the treatment of advanced breast cancer from a previous treatment regimen or clinical study within 14 days of the first dose of IMP
2. Concomitant medications or herbal supplements known to be strong inhibitors/inducers of cytochrome P450 (CYP) 3A4/5, sensitive CYP2B6 substrates, and drugs which are sensitive substrates of CYP2C9 and/or CYP2C19, and which have a narrow therapeutic index. In addition: Parts E and F will exclude the concomitant use of moderate CYP3A4 and/or Pgp inhibitors; Parts G H, I, J, K and L will exclude the concomitant use of moderate CYP3A4/5 inhibitors and inducers; Parts I and J will exclude concomitant use of sensitive substrates of CYP3A4 and/or CYP2D6 with a narrow therapeutic index."
3. Drugs known to prolong QT and known risk of Torsades de Pointes
4. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of IMP, except patients receiving radiotherapy to more than 30% of the bone marrow/a wide field of radiation within 4 weeks of the first dose of IMP
5. Major surgical procedure/significant traumatic injury, as judged by the investigator, within 4 weeks of the first dose of IMP, or an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the study.
2. Any unresolved toxicities from prior therapy \> CTCAE Grade 1 at the time of starting IMP, with the exception of alopecia.
3. Presence of life-threatening metastatic visceral disease, as judged by the investigator, uncontrolled CNS metastatic disease. Patients with spinal cord compression and/or brain metastases may be enrolled if definitively treated (eg, surgery or radiotherapy) and stable off steroids for at least 4 weeks prior to start of IMP
4. Past medical history of ILD (Parts E, F, K and L only)
5. Currently symptomatic radiotherapy-induced pneumonitis (Parts E, F, K and L only)
6. Evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus (HIV)
7. Any of the following cardiac criteria
1. Mean resting QTcF \>470 msec obtained from a triplicate ECG (≥450 msec for Parts K and L)
2. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, second- and third-degree heart block), or clinically significant sinus pause. Patients with controlled atrial fibrillation can be enrolled c) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as symptomatic heart failure, hypokalaemia, congenital long QT syndrome, immediate family history of long QT syndrome, or unexplained sudden death at \<40 years of age. Hypertrophic cardiomyopathy and clinically significant stenotic valve disease
(d) LVEF \<50% and/or experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, unstable angina pectoris, congestive heart failure NYHA Grade ≥2, cerebrovascular accident, or transient ischaemic attack.
(e) Uncontrolled hypertension. Hypertensive patients may be eligible but blood pressure must be adequately controlled at baseline.
(f) Uncontrolled hypotension - SBP \<90 mmHg and/or DBP \<50 mmHg for parts I \&J
8. Inadequate bone marrow reserve/organ function as demonstrated by any of the following lab values
1. ANC \<1.5 × 109/L
2. Platelet count \<100 × 109/L
3. Haemoglobin \<90 g/L
4. ALT \>2.5 × ULN
5. AST \>2.5 × ULN
6. TBL \>1.5 × ULN or \>3 × ULN in the presence of documented Gilbert's Syndrome
7. GFR \<50 mL/min
9. Clinically significant abnormalities of glucose metabolism, as defined by any of the following at screening (Parts I and J only):
1. Patients with diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment.
2. HbA1c ≥8.0% (63.9 mmol/mol).
