Comparison of Two Formulations of AZD5363 and the Effect of Food on Pharmacokinetic Exposure, Safety and Tolerability

Study Overview
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Brief Summary
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Comparison of Two Formulations of AZD5363 and the Effect of Food on Pharmacokinetic Exposure, Safety and Tolerability

Detailed Description
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This study is designed to investigate the safety, tolerability and pharmacokinetics of a new drug, AZD5363, in patients with advanced cancer . This study will investigate how the body handles AZD5363 (ie, how quickly the body absorbs and removes the drug), the comparison of a capsule and a tablet formulation and the effect of food on AZD5363 tablet formulation.

Official Title
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A Phase I, Open-Label, Multicentre Study to Compare Two Dosage Formulations of AZD5363 and to Establish the Effect of Food on the Pharmacokinetic Exposure, Safety and Tolerability of AZD5363 in Patients With Advanced Solid Malignancies

Conditions
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Advanced Solid Malignancy,, Safety and Tolerability,, Pharmacokinetics, Pharmacodynamics,, Tumour Response,

Intervention / Treatment
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* Drug: AZD5363
* Drug: AZD5363


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Aged at least 18 years The presence of a solid, malignant tumour, excluding lymphoma, that is resistance to standard therapies or for which no standard therapies exist The presence of at least one lesion 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 Estimated life expectancy of more than 12 weeks Exclusion Criteria: - Clinically significant abnormalities of glucose metabolism Spinal cord compression or brain metastases unless asymptomatic, treated and stable (not requiring steroids) Evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses or active infections including hepatitis B, C and Human Immunodeficiency Virus (HIV) Evidence of clinically significant cardiac abnormalities, uncontrolled hypotension, left ventricular ejection fraction below the lower limit of normal for the site or experience of significant cardiac interventional procedures A bad reaction to AZD5363 or any drugs similar to it in structure or class

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Formulation Switch<br>AZD5363 tablet twice daily followed by AZD5363 capsule twice daily on an intermittent regimen (4 days on, 3 days off). | Drug: AZD5363<br>* Oral AZD5363 twice daily, 4 days on 3 days off: tablet formulation for one week, followed by two weeks with capsule formulation.<br>|
| Experimental: Part B: Food effect<br>AZD5363 tablet twice daily on an intermittent regimen (4 days on, 3 days off) with/without food on one occasion | Drug: AZD5363<br>* Oral AZD5363 twice daily, 4 days on 3 days off, tablet formulation. On day 4 AZD5363 tablet without food. On day 11 AZD5363 tablet with food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of Css,Max for Day 4 to Day 11 | The actual sampling times were used in the pharmacokinetics (PK) parameter calculations and PK parameters were derived using standard non-compartmental methods. Following the twice daily dosing in Cycle 1 at Day 4 and 11 for both the formulation switch and food effect investigations, the following PK parameters have been determined: Maximum plasma concentration at steady state (Css max), time to Css,max (tss max), minimum plasma concentration at steady state (Css min), area under the plasma concentration-time curve from zero to the end of the dosing interval (AUCss) and apparent clearance (CLss/F). Css max, tss max were determined by inspection of the concentration-time profiles. AUCss was calculated using the linear up / log down trapezoidal rule. CLss/F was determined from the ratio of dose/AUCss. Ratio of Css,max for Day 4 to Day 11 have been derived. | Day 4 and Day 11 | 
| Ratio of AUCss for Day 4 to Day 11 | The actual sampling times were used in the parameter calculations and PK parameters were derived using standard non-compartmental methods. Following the twice daily dosing in Cycle 1 at Day 4 and 11 for both the formulation switch and food effect investigations, the following PK parameters have been determined: Css max, tss max, Css min, area under the plasma concentration-time curve from zero to the end of the dosing interval (AUCss) and CLss/F. Css max, tss max were determined by inspection of the concentration-time profiles. AUCss was calculated using the linear up / log down trapezoidal rule. CLss/F was determined from the ratio of dose/AUCss. Ratio of AUCss for Day 4 to Day 11 have been derived. | Day 4 and Day 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Best Objective Response (BOR) | Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 guidelines for measurable, non-measurable, target lesions (TLs) and non-target lesions (NTLs) and the objective tumour response criteria was used. Categorisation of objective tumour response assessment was based on the RECIST 1.1 guidelines for response: CR (complete response, efined as disappearance of all target lesions), PR (partial response, defined as >=30% decrease in the sum of the longest diameter of target lesions), SD (stable disease, defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression) and PD (progression of disease, defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion). BOR was the best overall response observed across the study and up to 36 weeks. Number of subjects with response (CR or PR) is described. | Assessed every 6 weeks, up to 36 weeks | 
| Efficacy: Disease Control at Week 12 | Disease control = confirmed complete response + confirmed partial response + stable disease at 12 weeks | Week 12 | 
| Efficacy: Target Lesion Size, Percentage Change From Baseline at Week 12 | Tumour size is the sum of the longest diameters of the target lesions. Target lesions are measurable tumour lesions. The percentage change in target lesion tumour size at each week 12 for which data are available was obtained for each subject taking the difference between the sum of the target lesion at each week 12 and the sum of the target lesions at baseline divided by the sum of the target lesions at baseline multiplied by 100 (i.e. (week 12) - baseline)/baseline * 100). | Week 12 | 
| Efficacy: Target Lesion Size, Best Percentage Change From Baseline | Tumour size is the sum of the longest diameters of the target lesions. Target lesions are measurable tumour lesions. best percentage change in tumour size from baseline is the maximum reduction from baseline or the minimum increase from baseline in the absence of a reduction from baseline based on all post baseline assessments. | Assessed every 6 weeks up to 36 weeks | 
| Efficacy: Progression-free Survival (PFS) | PFS is defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from randomised therapy or receives another anti-cancer therapy prior to progression. Subjects who have not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST assessment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions. | Assessed every 6 weeks up to 36 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid malignancy, AZD5363,, food effect,, formulation comparison