1. Postmenopausal women >= 18
2. WHO/ECOG perf. status 0-1
3. Histologically or cytologically proven diagnosis of breast cancer with evidence of
locally advanced or metastatic disease not amendable to resection or radiation
5. HER2 negative
6. Parts A & B: Must be eligible for fulvestrant. A maximum of 3 prior lines of
chemotherapy are allowed
7. Part C: Postmenopausal with locally advanced or metastatic ER+ breast cancer and
refractory to non steroidal aromatase inhibitors (NSAIs), defined as: disease
recurrence 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 of
end of letrozole, anastrazole, or exemestane, or exemestane treatment for locally
advanced or metastatic breast cancer.
8. Parts A, B3, and C: At least 1 lesion (measurable or non measurable) that can be
accurately assessed at baseline with CT or MRI and which is suitable for accurate
9. Parts B1 & B2: At least 1 lesion (measurable or non measurable), not previously
irradiated and not biopsied during screening that can be accurately assessed at
baseline as >= 10 mm in longest diameter (except lymph nodes which must have short
axis >= 15 mm) with CT or MRI and which is suitable for accurate repeated measurement
1. Prior chemotherapy, biological or radiation therapy, androgens, thalidomide,
immunotherapy, other anticancer agents, or any investigational drug or
corticosteroids within 14 days
2. Prior radiotherapy to >= 25% of bone marrow regardless of when it was received
3. Unresolved toxicity from prior therapy > 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 metabolising
enzymes 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
(>= 5 elimination half-life).
6. Previous treatment with AZD2014, AZD8055 or other mTORC1/2 inhibitor, fulvestrant, or
everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR
7. Major surgery or significant trauma within 4 weeks or anticipated need for major
surgery during the study, or minor surgery within 2 weeks of study entry
8. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or
leptomeningeal disease, as indicated by clinical symptoms, cerebral edema, and/or
progressive growth. History of CNS metastases or cord compression are eligible if
they have been definitively treated (e.g. radiotherapy, stereotactic surgery) and are
clinically stable, off anticonvulsants and steroids for at least 4 weeks. Not
eligible if they have spinal cord compression and/or brain metastases unless they are
asymptomatic or treated and stable off steroids for at least 4 weeks.
9. Any evidence of severe or uncontrolled systemic disease as judged by the
10. Any other malignancy within 3 years prior to study treatment, except for adequately
treated 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 bypass
graft, angioplasty, vascular stent, MI, angina, CHF (NYHA Grade >=2), ventricular
arrhythmias requiring continuous therapy, supraventricular arrhythmias including
atrial fibrillation, symptomatic pulmonary embolism, haemorrhagic or thrombotic
stroke, including TIA or any other CNS bleeding
12. Abnormal ECHO or MUGA at baseline (LVEF <50%)
13. Mean resting QTc > 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 12
14. Any clinically important abnormality in rhythm, conduction, or morphology of resting
ECG, e.g. complete left bundle branch block, third degree heart block.
15. Concomitant medications known to prolong QT, or with factors that increase the risk
of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia,
congenital long QT syndrome, family history of long QT syndrome, family history of
unexplained sudden death under age 40.
16. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following: ANC <1.5 x 109/L, platelets <100x109/L, haemoglobin <90g/L, ALT >2.5 x ULN
or >5 x ULN in the presence of liver metastases, total bilirubin >1.5 x ULN or >3 x
ULN in patients with Gilbert's Syndrome, serum creatinine >1.5 x ULN concurrent with
creatinine clearance <= 50 mL/min.
17. Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi
Syndrome or renal tubular acidosis.
18. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the
product, or previous significant bowel resection that would preclude adequate
absorption of AZD2014 or palbociclib.
19. History of hypersensitivity to active or inactive excipients of AZD2014, palbociclib
or 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 of
life-threatening complications in the short term including patients with massive
uncontrolled 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. The
primary prophylactic use of G-CSF is not permitted but it may be used to treat
Minimum Eligible Age: 18 Years
Maximum Eligible Age: 130 Years
Eligible Gender: Female