AZD2014 and Fulvestrant in Patients With ER+ Advanced Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess safety and tolerability of AZD2014 when given in combination with Fulvestrant

Detailed Description
-----------------
A Phase I, Open-label, Multicentre, Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD2014 Administered Orally in Combination with Intramuscular (IM) Fulvestrant to Patients with Estrogen Receptor Positive (ER+) Advanced, Metastatic Breast Cancer.

Official Title
-----------------
A Phase I, Open-label, Multicentre, Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of AZD2014 Administered Orally in Combination With Intramuscular (IM) Fulvestrant to Patients With Estrogen Receptor Positive (ER+) Advanced, Metastatic Breast Cancer

Conditions
-----------------
Advanced Metastatic Breast Cancer

Intervention / Treatment
-----------------
* Drug: AZD2014
* Drug: Fulvestrant


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of signed and dated written informed consent prior to any study specific procedures, sampling analysis Aged at least 18 At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by computerised tomography (CT) magnetic resonance imaging (MRI) or plain X-ray and is suitable for repeated assessment Histological or cytological confirmation of an ER+ advanced metastatic breast cancer tumour that is eligible for treatment with fulvestrant Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Patients must have evidence of non-child-bearing potential. Exclusion Criteria: Prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents, and any investigational agents within 14 days of starting study treatment (not including palliative radiotherapy at focal sites) Major surgery within 4 weeks prior to entry to the study (excluding placement of vascular access), or minor surgery within 2 weeks of entry into the study. Patients with severe cardiac condition of ischemia, impaired ventricular function and arrhythmias, evidence of severe or uncontrolled systemic or current unstable or uncompensated respiratory or cardiac conditions. Patients with diabetes type 1 or uncontrolled type II (HbA1c > 8% assessed locally)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD2014 with Fulvestrant<br>AZD2014 with Fulvestrant | Drug: AZD2014<br>* Single dose followed by multiple dosing or twice daily dosing for 2 days folllowed by 5 days off each week, or twice daily dosing on the first and fourth day of the week<br>Drug: Fulvestrant<br>* IM monthly after loading dose<br>* Other names: faslodex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | Up to 12 Months | 
| Adverse Events Leading to Dose Reduction of AZD2014 |  | Up to 28 Days | 
| Clinically Important Changes in Haematology Parameters |  | Up to 12 Months | 
| Clinically Important Changes in Clinical Chemistry Parameters |  | Up to 12 Months | 
| Left Ventricular Ejection Fraction |  | 24 hours | 
| QTcF Over 24 Hours |  | 24 hours | 
| Post-Baseline Glucose Elevation |  | 28 Days | 
| Sitting Diastolic Blood Pressure |  | 28 Days | 
| Sitting Systolic Blood Pressure |  | 28 Days | 
| Respiratory Rate |  | 28 Days | 
| Heart Rate |  | 28 Days | 
| Body Temperature |  | 28 Days | 
| Oxygen Saturation |  | 28 Days | 
| AZD2014 Peak Plasma Concentration at Steady State (Cmax,ss) on Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant |  | 5 Days | 
| AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-12) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant |  | 5 Days | 
| AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-24) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant |  | 5 Days | 
| AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-t) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant |  | 5 Days | 
| AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-∞) Cycle 0 Days -5 to -1, Continuous Dosing, no Fulvestrant |  | 5 Days | 
| AZD2014 Peak Plasma Concentration at Steady State (Cmax,ss) on Cycle 1 Day 15, BID Intermittent Dosing, With Fulvestrant |  | 15 Days | 
| Time to AZD2014 Peak Plasma Concentration at Steady State (Tmax,ss) on Cycle 1 Day 15, BID Intermittent Dosing, With Fulvestrant |  | 15 Days | 
| AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-12) Cycle 1 Day 15 Intermittent Dosing, With Fulvestrant |  | 15 Days | 
| AZD2014 Peak Plasma Concentration at Steady State (Cmax,ss) on Cycle 1 Day 22, Continuous Dosing, With Fulvestrant |  | 22 Days | 
| Time to AZD2014 Peak Plasma Concentration at Steady State (Tmax,ss) on Cycle 1 Day 22, Continuous Dosing, With Fulvestrant |  | 22 Days | 
| AZD2014 Area Under the Plasma Concentration Time Curve (AUC 0-12) Cycle 1 Day 22 Continuous Dosing, With Fulvestrant |  | 15 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AZD2014 Peak Plasma Concentration (Cmax) Following Single Dose, Fasted, no Fulvestrant. |  | 1 Day | 
| Time to AZD2014 Peak Plasma Concentration (Tmax) Following Single Dose, Fasted, no Fulvestrant. |  | 1 Day | 
| Area Under the Plasma Concentration-time Curve for AZD2014 From 0 to 12 Hours (AUC 0-12) Following Single Dose, Fasted, no Fulvestrant. |  | 1 Day | 
| Area Under the Plasma Concentration-time Curve for AZD2014 From 0 to Infinity (AUC 0-∞) Following Single Dose, Fasted, no Fulvestrant. |  | 1 Day | 
| Objective Response Rate | Objective Response Rate (ORR) is defined as the number (%) of patients with a confirmed overall response of either complete response (CR) or partial response (PR). | Up to 12 months | 
| Best Objective Response (BOR) | Best objective response was the best response a patient had following start of treatment but prior to starting any subsequent cancer therapy and prior to RECIST v1.1 progression or the last evaluable assessment in the absence of RECIST v1.1 progression. | Up to 12 months | 
| Duration of Response (DoR) | Duration of response is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression. | Up to 12 months | 
| Clinical Benefit Rate (CBR) at 24 Weeks | The Clinical Benefit Rate (CBR) at 24 weeks is defined as the percentage of patients who had a confirmed BOR of CR or PR in the first 24 weeks or who demonstrated SD for a minimum interval of 24 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e., 161 days) following the start of treatment. | Up to 12 months | 
| Percentage Change From Baseline at 16 Weeks in Target Lesion (TL) Size. | Baseline was defined as last evaluable assessment prior to starting treatment. Tumour size was the sum of the longest diameters of the target lesions. TLs are measurable tumour lesions. | Up to 12 months | 
| Progression Free Survival |  | Up to 12 months | 
| Progression Free Survival at 26 Weeks |  | Up to 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Estrogen receptor positive, Advanced metastatic breast cancer, Estrogen receptor positive advanced metastatic breast cancer