primary breast cancer MedDRA version: 18.1 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: AZD5363
Product Code: AZD5363
Pharmaceutical Form: Tablet
INN or Proposed INN: AZD5363
CAS Number: 1143532-39-1
Sponsors
University of Nottingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Provision of written informed consent WHO performance status 0-1 Able to swallow and retain oral medication Pre-menopausal (if surgically sterile or use acceptable contraception) or post-menopausal. Aged 18 years or over with histological confirmation of ER positive invasive breast carcinoma Stage 1/2/3 or Stage 4 with primary tumour in the breast amenable to biopsies scheduled to have chemotherapy (with or without surgery). New primary breast tumours (ipsi- or contra-lateral) despite prior endocrine treatment for an earlier primary breast tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1 are eligible. Tumours large enough to provide sufficient tissue to be taken by core-cut or tru-cut biopsy. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 60 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 90
Exclusion criteria
Exclusion criteria: 1 Any prior treatment for breast cancer except new primary breast tumours despite prior endocrine treatment for an earlier primary breast tumour with at least 12 months interval between cessation of endocrine therapy and Visit 1. 2 Known ER negative tumour. 3 Female patients with histological confirmation of ER positive invasive breast carcinoma not scheduled to have chemotherapy (with or without surgery) based on tumour characteristics and local treatment protocols 4 Exposure to potent inhibitors or inducers of CYP3A4 or CYP2D6 or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort). 5 Clinically significant abnormalities of glucose metabolism as defined by any of the following: ? Diagnosis of diabetes mellitus type I or II (irrespective of management). ? 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) ? Fasting Plasma Glucose = 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours. 6 Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment. 7 Spinal cord compression or brain metastases. 8 As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. 9 Any of the following cardiac criteria: ? Mean resting corrected QT interval (QTc) >450 msec obtained from 3 consecutive ECGs. ? Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block. ? Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, a history of congenital long QT syndrome, family history of long QT syndrome or a history of unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval. Further Information regarding this is given in Appendix 8. ? Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade 2. ? Uncontrolled hypotension – SBP 14 days prior to the determination of a haemoglobin =9 g/dL (=5.59 mmol/L)]. 13 Alanine aminotransferase (ALT) >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases. 14 Elevated Alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastasis and liver function is otherwise considered adequate in the investigator’s judgement. 15 Total bil
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: PRIMARY OBJECTIVE To compare the effect of three different dose levels of AZD5363 versus a placebo (dummy drug)on the reduction in the growth of cancer cells and the direct effect on selected biological markers of the AKT pathway of four and a half days treatment in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour using the biomarkers outlined below: • pPRAS40 • pGSK3b • Ki67 Stage 1 will compare 480mg BD versus placebo. Stage 2 will compare 360mg BD versus 240mg BD. ; Secondary Objective: SECONDARY OBJECTIVES 1) To compare the effect on the reduction in the growth of cancer cells and the direct effect on selected biological markers of the AKT pathway of four and a half days treatment of three different dose levels of AZD5363 versus placebo in oestrogen receptor positive breast cancers by measuring the biological changes in the tumour and circulation via measurement of: • Tumour pAKT • Platelet-rich plasma o Total and pPRAS40 o Total and pGSK3b o Total and pAKT • Tumour tissue o Cleaved caspase 3 o pS6 o FOXO3a 2) To measure tolerability and toxicity due to short term exposure to AZD5363. EXPLORATORY ANALYSES: It is envisaged that a number of tissue and blood based marker assays will be performed to assess if they provide any additional information on the activity of AZD5363 e.g. • Tissue markers e.g. PI3K, MAPK, HER2, PTEN, IGFR1, AR and total AKT • Blood markers – e.g. Autoantibodies to cancer associated antigens (especially those associated with ; Primary end point(s): Primary endpoints Changes in: | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1) Changes in alternative biological markers which relate to the AKT pathway. • Tumour pAKT • Tumour: cleaved caspase 3; pS6 (IHC); FOXO3a • Blood (platelet-rich plasma): Total and pPRAS40; Total and pGSK3b; Total and pAKT 2) the tolerability of AZD5363 as measured by incidence and severity of adverse events Exploratory Endpoints: To assess blood and tissue based markers related to other cellular pathways – for example: • Blood: Autoantibodies to cancer-associated antigens in the AKT pathway • Tumour: PI3K, MAPK, HER2, PTEN, IGFR1, AR and total AKT Safety endpoints The duration of treatment (4 and a half days) will be short in comparison to prior and ongoing studies of the compound and the known side effect profile makes it unlikely that a study of this duration will be stopped for toxicity reasons. Nevertheless side effects will be collected according to the NCI-CTC criteria and there will be an analysis of toxicity at the end of Stage 1 and again at the end of Stage 2. Stopping rules and discontinuation Efficacy: As this is a study of the short-term (four and a half days) exposure of the compound aiming to measure the biological (not clinical) effects, there will be no stopping rules based on clinical efficacy or futility analyses. Biological endpoints: During stage 1 analysis all the biological markers which are listed as primary endpoints will commence during the recruitment period. These biomarker measurements will be completed as swiftly as possible after stage 1 has finished. Analyses of these biomarker data obtained through Stage 1 will be performed as swiftly as possible. Stage 2 will continue if the DSMC decide that significant knockdown by AZD5363 (as pre-defined) in terms o | — |
Countries
United Kingdom
Contacts
Public ContactProfessor J F R Robertson
University of Nottingham
Outcome results
None listed