Clinical Trials

Inclusion:
1. Postmenopausal women Greater than Equal 18
2. WHO/ECOG perf. status 0-1
3. Histologically or cytologically proven diagnosis of breast cancer with evidence oflocally advanced or metastatic disease not amendable to resection or radiation
4. ER+
5. HER2 negative
6. Parts A & B: Must be eligible for fulvestrant. A maximum of 3 prior lines ofchemotherapy are allowed
7. Part C: Postmenopausal with locally advanced or metastatic ER+ breast cancer andrefractory to non steroidal aromatase inhibitors (NSAIs), defined as: diseaserecurrence while on, or within 12 months of end of adjuvant treatment with letrozole,anastrazole, or exemestane; or disease progression while on, or within one month ofend of letrozole, anastrazole, or exemestane, or exemestane treatment for locallyadvanced or metastatic breast cancer.
8. Parts A, B3, and C: At least 1 lesion (measurable or non measurable) that can beaccurately assessed at baseline with CT or MRI and which is suitable for accuraterepeated measurement
9. Parts B1 & B2: At least 1 lesion (measurable or non measurable), not previouslyirradiated and not biopsied during screening that can be accurately assessed atbaseline as Greater than Equal 10 mm in longest diameter (except lymph nodes which must have shortaxis Greater than Equal 15 mm) with CT or MRI and which is suitable for accurate repeated measurement Exclusion:
1. Prior chemotherapy, biological or radiation therapy, androgens, thalidomide,immunotherapy, other anticancer agents, or any investigational drug orcorticosteroids within 14 days
2. Prior radiotherapy to Greater than Equal 25% of bone marrow regardless of when it was received
3. Unresolved toxicity from prior therapy Greater than CTCAE grade 1
4. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5, CYP2C8, Pgp (MDR1)or BCRP if taken within the stated washout period prior to start of treatment
5. Exposure to sensitive or narrow therapeutic range substrates of the drug metabolisingenzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6, or other drug transporters Pgp (MDR1), BCRP,OATP1B1, OATP1B3, OCT1 and OCT2 within the appropriate wash-out period for each drug( Greater than Equal 5 elimination half-life).
6. Previous treatment with AZD2014, AZD8055 or other mTORC1/2 inhibitor, fulvestrant, oreverolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTORpathway
7. Major surgery or significant trauma within 4 weeks or anticipated need for majorsurgery during the study, or minor surgery within 2 weeks of study entry
8. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, orleptomeningeal disease, as indicated by clinical symptoms, cerebral edema, and/orprogressive growth. History of CNS metastases or cord compression are eligible ifthey have been definitively treated (e.g. radiotherapy, stereotactic surgery) and areclinically stable, off anticonvulsants and steroids for at least 4 weeks. Noteligible if they have spinal cord compression and/or brain metastases unless they areasymptomatic or treated and stable off steroids for at least 4 weeks.
9. Any evidence of severe or uncontrolled systemic disease as judged by theInvestigator.
10. Any other malignancy within 3 years prior to study treatment, except for adequatelytreated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
11. Any of the following currently or within 12 months: coronary/peripheral artery bypassgraft, angioplasty, vascular stent, MI, angina, CHF (NYHA Grade Greater than Equal 2), ventriculararrhythmias requiring continuous therapy, supraventricular arrhythmias includingatrial fibrillation, symptomatic pulmonary embolism, haemorrhagic or thromboticstroke, including TIA or any other CNS bleeding
12. Abnormal ECHO or MUGA at baseline (LVEF Less than 50%)
13. Mean resting QTc Greater than 470 msec, family or personal history of long or short QT syndrome,Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12months
14. Any clinically important abnormality in rhythm, conduction, or morphology of restingECG, e.g. complete left bundle branch block, third degree heart block.
15. Concomitant medications known to prolong QT, or with factors that increase the riskof QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia,congenital long QT syndrome, family history of long QT syndrome, family history ofunexplained sudden death under age 40.
16. Inadequate bone marrow reserve or organ function as demonstrated by any of thefollowing: ANC Less than 1.5 x 109/L, platelets Less than 100x109/L, haemoglobin Less than 90g/L, ALT Greater than 2.5 x ULNor Greater than 5 x ULN in the presence of liver metastases, total bilirubin Greater than 1.5 x ULN or Greater than 3 xULN in patients with Gilbert's Syndrome, serum creatinine Greater than 1.5 x ULN concurrent withcreatinine clearance Less than Equal 50 mL/min.
17. Pre-existing renal disease including glomerulonephritis, nephritic syndrome, FanconiSyndrome or renal tubular acidosis.
18. Refractory nausea and vomiting, chronic GI diseases, inability to swallow theproduct, or previous significant bowel resection that would preclude adequateabsorption of AZD2014 or palbociclib.
19. History of hypersensitivity to active or inactive excipients of AZD2014, palbociclibor fulvestrant, or drugs with a similar chemical structures
20. Patients with Diabetes Type I or uncontrolled Type II
21. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk oflife-threatening complications in the short term including patients with massiveuncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis,and over 50% of liver involvement in metastases.
22. Prior hematopoietic stem cell or bone marrow transplant
23. Patients receiving regular coumadin therapy (LMW heparin is allowed)
24. Known coagulation abnormalities
25. Erythropoietin, G-CSF, and GM-CSF are not allowed within 2 weeks prior to study. Theprimary prophylactic use of G-CSF is not permitted but it may be used to treattreatment-emergent neutropenia.