This is an open-label, multicentre, 4-arm randomised phase II trial of fulvestrant + AZD2014
versus fulvestrant + everolimus versus fulvestrant alone in patients with ER-positive,
HER2-negative advanced or metastatic breast cancer, whose disease relapsed during treatment
with (or within 12 months after discontinuation of) an AI in the adjuvant setting or
progressed during treatment with an AI in the metastatic setting. Patients will be randomised
(2:3:3:2) to one of the four treatment arms:
- Fulvestrant + AZD2014 (continuous daily schedule)
- Fulvestrant + AZD2014 (intermittent schedule - 2 days on, 5 days off)
- Fulvestrant + everolimus
Randomization will be stratified by the following criteria:
- Measurable disease (vs. non-measurable).
- Sensitivity to prior endocrine therapy (sensitive versus resistant) Sensitivity to prior
endocrine therapy is defined as (i) at least 24 months of endocrine therapy before
recurrence in the adjuvant setting or (ii) a complete or partial response to prior
metastatic endocrine treatment, or (iii) stabilization for at least 24 weeks of
endocrine therapy for advanced disease.
Treatment will be continued until disease progression unless there is evidence of
unacceptable toxicity or if the patient requests to be withdrawn from the study. If one of
the treatments (fulvestrant or mTOR inhibitor) is discontinued prior to disease progression,
patients should be continued on single agent treatment until progression, evidence of
unacceptable toxicity or if the patient requests to be withdrawn from the study.
At the time of documented disease progression (using RECIST 1.1), patients randomised to
receive fulvestrant + everolimus who still meet eligibility criteria may be permitted to
receive open-label crossover treatment with fulvestrant + AZD2014. Crossover therapy must
begin no later than 28 days after the clinic visit at which progression was determined.
Patients will receive crossover therapy until progression, intolerable toxicity, elective
withdrawal from the study, or until the completion or termination of the study, whichever
Tumour evaluations will be performed before the initiation of treatment, every 8 weeks during
the first 40 weeks and every 12 weeks thereafter until disease progression.
The study will also assess the relationship between the anticipated anti-tumour activity of
the treatment regimen and biological characteristics of patients' tumour at baseline
1. Written informed consent prior to admission to this study
2. Women, age ≥18 years
3. Histologically confirmed breast cancer
4. Metastatic or locally recurrent disease; locally recurrent disease must not be
amenable to resection with curative intent (patients who are considered suitable for
surgical or ablative techniques following potential down-staging with study treatment
are not eligible).
5. Patients must have:
1. at least one lesion, not previously irradiated, that can be measured accurately
at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have
short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging
(MRI) which is suitable for accurate repeated measurements, or
2. lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable
disease as defined above; patients with sclerotic/osteoblastic bone lesions only
in the absence of measurable disease are not eligible
6. Radiological or clinical evidence of recurrence or progression
7. ER-positive disease, defined as tumour cells being positive for ER with ≥ 1% of tumour
cells positive for ER on IHC or IHC score (Allred) of ≥ 3
8. HER2-negative disease with 0, 1+ or 2+ intensity on IHC and no evidence of
amplification on ISH.
9. Formalin fixed, paraffin embedded tumour sample from the primary and/or recurrent
cancer must be available for central testing
10. Postmenopausal women. Women will be considered postmenopausal if they meet one of the
1. Age ≥ 50 years and 1 year or more of amenorrhea
2. Age < 50 years and 1 year or more of amenorrhea, with an estradiol assay <
3. Age < 50 with prior hysterectomy but intact ovaries with an estradiol assay <
4. Status after bilateral oophorectomy (≥ 28 days prior to first study treatment)
Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone
(LHRH) agonist (goserelin acetate or leuprolide acetate) is not permitted for
induction of ovarian suppression.
Each patient must meet all of the following inclusion criteria to be enrolled in the
11. Disease refractory to aromatase inhibitors (AI), defined as
1. Disease recurrence while on, or within 12 months of end of adjuvant treatment
with letrozole, anastrozole, or exemestane.
2. Progression while on, or within one month of end of letrozole, anastrozole or
exemestane treatment for locally advanced or metastatic Breast Cancer.
Note: Any number of lines of hormonal therapy before or after AI therapy is allowed.
Note: Letrozole, anastrozole or exemestane do not have to be the last treatment prior
12. Haematologic and biochemical indices within the ranges shown below. These measurements
must be performed within one week prior to randomisation
1. ANC ≥ 1500 cells/μl, haemoglobin ≥ 9g/dl, and platelet count ≥ 100000/μl.
2. Serum Creatinine < 1.5 times ULN concurrent with creatinine clearance ≥ 50ml/min
(measured or calculated by Cockcroft and Gault equation), confirmation of
creatinine clearance is only required when creatinine is > 1.5 times ULN.
3. Bilirubin level < 1.5 x ULN if no demonstrable liver metastases or < 3 times ULN
in the presence of liver metastases.
4. AST or ALT < 2.5 x ULN.
5. International normalized ratio (INR) < 1.5 and activated partial thromboplastin
time (aPTT) < 1.5 x ULN; for patients requiring therapeutic anticoagulation
therapy, a stable INR ≤ 2.5 x ULN is required to mitigate potential bleeding.
6. No clinically relevant and treatment resistant abnormalities in potassium,
sodium, calcium (corrected for plasma albumin) or magnesium.
7. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤
2.5 ×ULN. In case one or both of these thresholds are exceeded, the patient can
only be included after initiation of statin therapy and when the above mentioned
values have been achieved.
13. ECOG performance status 0-2
14. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had a hysterectomy, bilateral oophorectomy, bilateral
tubular ligation or is post-menopausal (total cessation of menses for ≥ 1 year
1. Presence of life-threatening metastatic visceral disease, defined as extensive hepatic
involvement or any degree of brain or leptomeningeal involvement (past or present), or
symptomatic pulmonary lymphangitic spread. Patients with discrete pulmonary
parenchymal metastases are eligible, provided their respiratory function is not
compromised as a result of disease.
2. More than one line of prior chemotherapy for metastatic breast cancer Note: A
chemotherapy line in advanced disease is an anticancer regimen(s) that contains at
least 1 cytotoxic chemotherapy agent and given for 21 days or longer. If a cytotoxic
chemotherapy regimen was discontinued for a reason other than disease progression and
lasted less than 21 days, then this regimen does not count as a "prior line of
3. Prior chemotherapy, biological therapy, androgens, thalidomide, immunotherapy, other
anticancer agents or any investigational agents within 14 days of starting study
treatment (not including palliative radiotherapy at focal sites), radiotherapy with a
wide field of radiation (greater than or equal to 30% marrow or whole pelvis or spine)
within 4 weeks of starting study treatment, or strontium-90 (or other
radiopharmaceuticals) within the past 3 months or major surgery within 4 weeks prior
to entry into the study (excluding the placement of vascular access); with the
exception of alopecia, all unresolved toxicities from prior treatment should be no
greater than CTCAE grade 1 at the time of starting study treatment
4. Prior treatment with fulvestrant or everolimus
5. Prior treatment with PI3K inhibitors, Akt inhibitors or other mTOR inhibitors.
6. Patients receiving concomitant immunosuppressive agents or chronic systemic
corticosteroids (≥10 mg prednisolone or an equivalent dose of other anti-inflammatory
corticosteroids) use for ≥28 days at the time of study entry except in cases outlined
below: Topical applications (e.g. rash), inhaled sprays (e.g. obstructive airways
diseases), eye drops or local injections (e.g. intra-articular) are allowed. Patients
on stable low dose of corticosteroids for at least two weeks before randomisation are
7. Current refractory nausea and vomiting, chronic gastrointestinal disease or inability
to swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of the study medication
8. Clinically significant pulmonary dysfunction
9. Significant cardiovascular disease; patients who have experienced any of the following
procedures or conditions currently or in the preceding 12 months are excluded:
1. History of myocardial infarction, acute coronary syndromes (including unstable
angina), or history of coronary angioplasty/stenting/bypass grafting.
2. History of symptomatic congestive heart failure (CHF) New York Heart Association
(NYHA) Classes II-IV or LVEF <50% by either ECHO or MUGA
3. Severe cardiac arrhythmia requiring medication or severe conduction abnormalities
4. Poorly controlled hypertension (resting diastolic blood pressure >100 mmHg)
5. Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy,
10. QTc prolongation defined as a QTc interval >470 msecs or other significant ECG
abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia
(ventricular rate <50 beats/min)
11. Concomitant medications known to prolong QT interval, or with factors that increase
the risk of QTc prolongation or risk of arrhythmic events (such as heart failure,
hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or
unexplained sudden death under 40 years of age)
12. Clinically significant abnormalities of glucose metabolism as defined by any of the
1. Diagnosis of diabetes mellitus type I (irrespective of management).or
uncontrolled diabetes mellitus type II
2. Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (64 mmol/mol) (conversion
equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C (%) - 2.15] x 10.929)
13. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 within 2 weeks
before the first dose of study treatment (3 weeks for St John's Wort and 5 weeks for
phenobarbitone) (for details please refer to Appendix 6).
1. Inhibitors (competitive): ketoconazole, itraconazole, indinavir, saquinovir,
nelfinavir, atazanavir, amprenavir, fosamprenavir, troleandomycin, telithromycin,
fluconazole, nefazodone, cimetidine, aprepitant, miconazole, fluvoxamine,
P-glycoprotein, grapefruit juice, or seville oranges (1 week minimum wash-out
period), amiodarone (27 week minimum wash-out period)
2. Inhibitors (time dependent): erythromycin, clarithromycin, verapamil, ritonavir,
diltiazem (2 week minimum wash-out period)
3. Inducers: phenytoin, rifampicin, St. John's Wort, carbamazepine, dexamethasone,
primidone, griseofulvin, carbamazepine, barbiturates, troglitazone, pioglitazone,
oxcarbazepine, nevirapine, efavirenz, rifabutin (3 week minimum wash-out period)
and phenobarbitone (5 week minimum wash-out period)
14. Exposure to potent or moderate inhibitors or inducers of CYP2C8 within 1 week before
the first dose of study treatment (for details please refer to Appendix 6).
a. Inhibitors: Gemfibrozil, trimethoprim, glitazones, montelukast, quercetin (1 week
minimum wash-out period)
15. Application of haemopoietic growth factors (e.g. G-CSF, GM-CSF) within 2 weeks before
receiving study drug
16. Any other disease, metabolic dysfunction, physical examination finding, or clinical
laboratory finding that, in the investigator's opinion, gives reasonable suspicion of
a disease or condition that contraindicates the use of an investigational drug, may
affect the interpretation of the results, render the patient at high risk from
treatment complications or interferes with obtaining informed consent.
17. History of hypersensitivity to active or inactive excipients of AZD2014 or everolimus
or drugs with a similar chemical structure or class to AZD2014 or everolimus
18. History of hypersensitivity to active or inactive excipients of fulvestrant and/or
19. Patients presenting with anaemia symptoms (haemoglobin ≤ 90 g/L).
20. Currently receiving (and are unwilling to discontinue) oestrogen replacement therapy
(last dose ≤ 7 days prior to randomisation)
21. Psychological, familial, sociological or geographical conditions that do not permit
compliance with the study protocol.
22. Detained persons or prisoners
23. Pregnant or nursing women (including no breast feeding from two weeks before the first
dose of study medication, till 8 weeks after the last dose of study medication).