This dose finding/extension study was designed originally to consist of three parts: Part A
was intended to identify the MTD of the AZD2014/ palbociclib combination on a background of
fulvestrant (referred to as the triplet) in postmenopausal women with locally advanced/
metastatic estrogen receptor positive (ER+) breast cancer. Part B was to further characterize
safety, tolerability, PK, and preliminary efficacy in single-arm dose expansion groups. Part
C was to be a Phase 2, randomized, double-blind, extension comparing the triplet and doublet
combinations. Part C was deleted from the protocol and was not performed.
This dose finding/extension study was designed originally to consist of three parts:
Part A is a Phase 1 triplet-dose finding investigation in 3-6 patients per cohort to
determine the maximum tolerated dose (MTD) of the triplet.
Part B is a single arm expansion in approximately 27 patients evaluable for response to
define the recommended Phase 2 dose (RP2D).
Part C was intended to investigate the efficacy of the triplet combination at the RP2D in a
randomized, double-blind, placebo-controlled, stratified, parallel group extension. Part C
was intended to include ER+, locally advanced and/or metastatic breast cancer patients who
have progressed following prior non-steroidal aromatase inhibitor (NSAI) endocrine therapy.
Patients in Part C were to be randomized to receive either the triplet combination (AZD2014 +
palbociclib + fulvestrant) or the doublet (matching AZD2014 placebo + palbociclib +
fulvestrant). Patients were to be stratified according to hormone sensitivity, presence of
visceral metastases, and prior CDK inhibitor treatment. Part C would have been conducted if
indicated by the emerging data.
Inclusion:
1. Signed and dated written informed consent prior to any mandatory study specific
procedures, sampling and analyses.
2. Signed and dated written informed consent for tumour biopsies. If the tumour is found
not to be safely accessible the biopsy will not be taken. Accessible lesions are
defined as those which are biopsiable and amenable to repeat biopsy, unless clinically
contraindicated. In this case the patient will remain in the study and there will be
no penalty or loss of benefit to the patient and they will not be excluded from other
aspects of the study.
3. Postmenopausal women aged ≥ 18 years
4. Negative pregnancy test prior to dosing and willing to use a highly effective method
of contraception for the duration of the study and for 90 days after the last dose of
IP if they are under 50 unless they have medically confirmed irreversible premature
ovarian failure, bilateral oophorectomy, bilateral salpinectomy, or complete or
partial hysterectomy.
Highly effective methods of contraception are:
• Use of oral, injected or implanted hormonal methods of contraception which inhibit
ovulation, either estrogen and progestogen containing intravaginal, transdermal) or
only progesterone containing (oral, injectable, implantable)
• Placement of an intrauterine device (IUD or intrauterine system (IUS)
• True abstinence
- Bilateral tubal ligation
- Vasectomised partner
5. World Health Organisation/Eastern Cooperative Oncology Group (ECOG) performance status
of patient is 0-1 with no deterioration over the previous 2 weeks and minimum life
expectancy of 12 weeks.
6. Histologically or cytologically proven diagnosis of breast cancer with evidence of
locally advanced or metastatic disease, not amenable to resection or radiation therapy
with curative intent.
7. Documentation of estrogen receptor positive (ER+) breast cancer based on most recent
tumour biopsy (unless bone-only disease).
8. Documented human epidermal growth factor receptor 2 negative (HER2-) tumor on most
recent tumor biopsy.
9. Where regionally permitted, all patients must agree to provide if available a
formalin-fixed paraffin embedded (FFPE) tissue biopsy sample taken at the time of
presentation with recurrent or metastatic disease.
10. At least one lesion (measurable and/or non measurable) that can be accurately assessed
at baseline with computerised tomography (CT) or magnetic resonance imaging (MRI)
which is suitable for accurate repeated measurements.
11. Meet the following study part specific criteria related to previous therapy for breast
cancer:
For Part A: Postmenopausal patient suitable for fulvestrant. Patient is allowed to have a
maximum of 3 prior lines of chemotherapy. Previous treatment with CDK4/6 inhibitors is
allowed
For Part B: Postmenopausal patient with locally advanced or metastatic ER+ve breast cancer
and refractory to AIs defined as:
- Disease recurrence while on, or within 12 months of end of adjuvant treatment with
letrozole, anastrozole, or exemestane, or
- Disease progression while on, or within one month of end of letrozole, anastrozole or
exemestane treatment for locally advanced or metastatic breast cancer
- Letrozole or anastrozole do not have to be the last treatment prior to
randomization.
- Patients who received one prior chemotherapy line for advanced/metastatic breast
cancer are allowed.
Previous treatment with fulvestrant (or letrozole) is allowed. Other prior anticancer
therapy (e.g. tamoxifen) are also allowed.
For inclusion in the optional research component:
1. Genetic research: Provision of signed and dated written consent for genetic research
sampling and analyses. If a patient declines to participate in genetic component of
the study, there will be no penalty or loss of benefit to the patient. The patient
will not be excluded from other aspects of the study described in this Clinical Study
Protocol, so long as they consent to the main study.
Exclusion:
1. Prior chemotherapy, biological therapy, radiation therapy, or immunotherapy,
androgens, thalidomide, other anticancer agents, investigational drug or
corticosteroids within 14 days. Patients who received prior radiotherapy to >= 25% of
bone marrow are not eligible independent of when it was received. Patients is not
eligible if there are unresolved toxicities from prior therapy > CTCAE grade 1 at the
start of study treatment with the exception of alopecia.
2. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) or BCRP
within stated washout periods.
3. Exposure to sensitive or narrow therapeutic range substrates of drug transporters
OATP1B1, OATP1B3, MATE1 and MATE2K within wash-out period (5 x elimination half-life).
4 Exposure to proton pump inhibitors within wash-out period (5 x elimination half-life).
5. Previous AZD2014, AZD8055 or other dual mTORC1/2 inhibitor
- In Part B only: Prior treatment with CDK4/6, or everolimus or any PI3K-mTOR pathway
6. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis,
or leptomeningeal disease. Patients with a history of CNS metastases or cord
compression are eligible if definitively treated and clinically stable and off
anticonvulsants and steroids for at least 4 weeks. Patients are not eligible if there
is spinal cord compression and/or brain metastases, unless asymptomatic or treated and
stable and off steroids for at least 4 weeks.
7. Evidence of severe or uncontrolled systemic diseases such as:
• Severe hepatic impairment
• Interstitial lung disease (bilateral, diffuse, parenchymal lung disease)
- Current unstable or uncompensated respiratory or cardiac conditions
- Uncontrolled hypertension
- Active bleeding diatheses
- Any active infection
8. Other malignancy within 3 years, except adequately treated basal cell or
squamous cell skin cancer, or carcinoma in situ of the cervix
9. Experienced any of the following currently or in the last 12 months:
- Coronary/peripheral artery bypass graft
- Angioplasty
- Vascular stent
- Myocardial infarction
- Angina pectoris
- Congestive heart failure NYHA Grade ≥ 2
- Ventricular arrhythmias requiring continuous therapy
- Supraventricular arrhythmias including atrial fibrillation of any grade
- Symptomatic pulmonary embolism
- Haemorrhagic or thrombotic stroke
10. Abnormal ECHO or MUGA at baseline (LVEF <50%).
11. 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 months.
12. Clinically important abnormalities in rhythm, conduction or morphology of
resting ECG.
13. Hepatitis B (HBV), Hepatitis C (HCV) or Human Immunodeficiency virus (HIV).
14. Concomitant medications known to predispose to Torsade de Pointes, or factors
that increase the risk of QT prolongation or risk of arrhythmic events such as:
- Heart failure
- Hypokalaemia
- Congenital long QT syndrome
- Family history of long QT syndrome
- Family history of unexplained sudden death under 40 years-of-age
15. Inadequate bone marrow reserve or organ function as demonstrated by:
- ANC <1.5 x 10^9/L.
- In Part A only - Cohorts of patients with specific baseline ANC range to be
enrolled defined as follows: I) Low ANC patients: between 1.5 x 10^9/L and 3.0 x
10^9/L; ii) High ANC patients > 3.0 x 10^9/L.
- Platelets <100 x 10^9/L
- Haemoglobin <90 g/L
- ALT >2.5 x ULN or > 5 x ULN in the presence of liver mets.
- AST >2.5 x ULN or > 5 x ULN in the presence of liver mets.
- Total bilirubin >1.5 x ULN. Total bilirubin >3 x ULN in patients with documented
Gilbert's Syndrome.
- Serum creatinine >1.5 x ULN concurrent with creatinine clearance ≤50 mL/min.
16. Pre-existing renal disease including glomerulonephritis, nephritic syndrome,
Fanconi Syndrome or Renal tubular acidosis.
17. Refractory nausea/vomiting, chronic GI diseases, inability to swallow the
product or previous significant bowel resection.
18. Hypersensitivity to excipients of AZD2014, Palbociclib or Fulvestrant or
drugs with a similar structure.
19. Diabetes Type I or uncontrolled Type II, as defined in WHO 2006 (fasting
serum glucose of > 7.0 mmol/L [126 mg/dL]).
20. Patient 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.
21. Prior hematopoietic stem cell or bone marrow transplant.
22. Regular coumadin therapy. Low-molecular-weight heparin therapy or oral Factor
Xa antagonists are allowed.
23. Known abnormalities in coagulation, e.g. bleeding diathesis.
24. Hematopoietic growth factors (such as erythropoietin, granulocyte colony
stimulating factor [G-CSF], granulocyte macrophage colony stimulating factor
[GM-CSF]) within 2 weeks prior. Primary prophylactic use of G-CSF is not
permitted.
25. Other severe acute or chronic psychiatric condition that may increase the
risks associated with study participation.
