Locally advanced or metastatic estrogen receptor positive breast cancer
Conditions
Interventions
Product Name: AZD2014 Film-Coated Tablet 10mg
Product Code: AZD2014
Pharmaceutical Form: Film-coated tablet
CAS Number: 1009298-59-2
Cur
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 mandatory tumour biopsies. If the tumour is found not to be safely accessible the biopsies will not be taken. Accessible lesions are defined as those which are biopsiable and amenable to repeat biopsies, 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 b
Exclusion criteria
Exclusion criteria: 1. Prior chemotherapy, biological, radiation, or immunotherapy, androgens, thalidomide, other anticancer agents, investigational drug or corticosteroids = 25% of bone marrow are not eligible. Patients are not eligible if there are unresolved toxicities from prior therapy > CTCAE grade 1 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 PPIs 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 - In Part C only: Prior treatment with fulvestrant, or with everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway. 6. Active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease. Patients with CNS metastases or cord compression are eligible if definitively treated and clinically stable and off anticonvulsants & steroids for >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 >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 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 patie
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The amended primary objectives for parts A and B are to investigate the safety and tolerability of the combination of AZD2014 and palbociclib on a background of fulvestrant in patients with locally advanced/metastatic ER+ve breast cancer and to define the combination dose(s)/schedule(s) for further clinical evaluation.; Secondary Objective: PART A: To assess the anti-tumour activity of the triplet by evaluation of tumour response (best objective response, objective response rate, clinical benefit rate and change in tumor size) using RECIST version 1.1 PART B: To assess anti-tumour activity and efficacy of the triplet by evaluation of PFS, tumour response (BOR, ORR, DoR, CBR PFS and change in tumor size) by RECIST version 1.1 & overall survival. PART A: To characterise the single dose and multiple dose PK of AZD2014 and palbociclib administered as the triplet combination. PART B: To characterise the multiple dose PK of AZD2014 and palbociclib administered as the triplet combination. PARTS A & B: To obtain preliminary assessment of the triplet activity in tumour by evaluation of PD biomarker changes including pS6 & pAKT. ; Primary end point(s): 1. Primary Endpoints for Parts A and B: The incidence of Dose Limiting Toxicities (DLTs), and the occurrence of adverse events, and changes in vital signs, clinical chemistry and haematology, coagulation parameters, and ECGs. 2. Primary Endpoint for Part C: Progression Free Survival (PFS) according to RECIST v 1.1. ; Timepoint(s) of evaluation of this end point: 1. AEs/vitals every visit until 28 days after last AZD2014/Palbo dose. SAEs until 250 days after last Fulvestrant dose. Blood collected Day 1, (2), 8, 15, 22 in Cycles 1 and 2; Day 1 and 15 of Cycles 3 and 4; Day 1 of each cycle thereafter to assess changes in clinical chemistry, haematology, coagula | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Part A: Anti-tumour activity of the triplet according to investigator assessment of BOR, ORR, CBR, and percentage change in tumour size. 2. Part B: Anti-tumour activity and efficacy of the triplet according to RECIST v1.1 by investigator assessment of BOR, ORR, DoR, CBR, percentage change in tumour size, and PFS and OS. 3. Parts A: Plasma AZD2014 and palbociclib single dose concentrations and derived PK parameters 4. Parts A and B: Plasma AZD2014 and palbociclib multiple dose concentrations and derived PK parameters 5. Parts A and B: Evaluation of pharmacodynamic biomarker changes including pS6 and pAKT by determining percentage change from baseline in H score. ; Timepoint(s) of evaluation of this end point: 1. Every 8 wks 2. Every 8 wks. CBR will be assessed at 24 weeks. Survival will be assessed every 12 wks. 3. Samples for single-dose PK will be collected at prespecified times on PK days for AZD2014 and palbociclib. 4. Samples for multiple-dose PK will be collected at prespecified times on PK days for AZD2014 and palbociclib at steady state. 5. Biomarker analysis will be done every 4 weeks. | — |
Countries
United Kingdom, United States
Contacts
Public ContactInformation Centre
AstraZeneca AB
Outcome results
None listed