Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Preliminary Efficacy of AZD2014

Study Overview
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Brief Summary
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The main purpose of the study is to establish a safe dose of the drug by providing information on any potential side effects this drug may cause and collecting data about how a patient's cancer responds to the drug. The study will also assess the blood levels and action of AZD2014 in the body over a period of time and will indicate whether the drug has an effect on the types of cancer the patients have.

Official Title
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A Phase I, Open Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the mTor Kinase Inhibitor AZD2014 Administered Orally to Patients With Advanced Solid Malignancies

Conditions
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Advanced Solid Malignancies

Intervention / Treatment
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* Drug: AZD2014


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological confirmation of a solid, malignant tumour that is refractory to standard therapies or for which no standard therapies exist 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 World Health Organisation performance status 0-2 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks Exclusion Criteria: Patients with severe laboratory abnormalities for haematology, liver or renal function. Also treatment with any haemopoietic growth factors are not allowed within two weeks prior to first dose of study drug Patients with abnormal fasting glucose, type I or uncontrolled type II diabetes 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 150 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD2014<br>AZD2014 dose escalation phase in Part A and expansion phase in Part B. | Drug: AZD2014<br>* Dose escalation phase: a single dose taken orally (solution or tablet) of AZD2014 on single dose day 1 (visit 2), followed by once or twice daily continuous dosing after a washout period (48 hours - 7 days) at visit 4, until discontinuation or withdrawal or Single or multiple doses taken orally (solution or tablet) of AZD2014 taken intermittently until discontinuation or withdrawal. Expansion phase: twice daily dosing from day 1 until discontinuation or withdrawal or a single dose taken orally of AZD2014 on single dose day 1 (visit 2), followed by a single dose on second single dose day 1 (visit 3) after a washout period (48 hours - 7 days) followed by once or twice daily continuous dosing after a washout period (48 hours - 7 days) at visit 4, until discontinuation or withdrawal or single or multiple doses taken orally (solution or tablet) of AZD2014 taken intermittently until discontinuation or withdrawal.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Maximum Tolerated Dose (MTD) was determined by testing various doses and schedules of AZD2014 in cohorts of 3-6 evaluable patients. MTD reflects the highest dose of drug at each schedule that did not cause a DLT in >1 patient | Up to 21 days from first multiple dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Objective Response | Best Objective Response per Response Evaluation Criteria in Solid Tumours Criteria (RECIST) 1.1 for target and non target lesions assessed by CT, MRI or X-ray; Complete Response (CR), Disappearance of all target lesions since baseline; Partial Response (PR), At least a 30 percent decrease in the sum of diameters of target lesions; Progressive Disease (PD), At least a 20 percent increase in the sum of diameters of target lesions and an absolute increase of at least 5mm | Assessed every 8 weeks until progression or withdrawal, whichever came first, estimated to be up to 4 months | 
| Maximum Concentration (Cmax) Single Dose | Maximum concentration following single dose (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Following Single Dose up to 12, 24 or 48 hours post dose | 
| Area Under the Curve (AUC) Single Dose | Area under the curve following single dose Continuous dosing - AUC parameter used Intermittent dosing - AUC(0-12) used (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Following Single Dose up to 12, 24 or 48 hours post dose | 
| Maximum Concentration (Cmax) at Steady State | Cmax at steady state (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Multiple dosing to steady state (up to 12 or 48 hours post dose) | 
| Area Under the Curve (AUC) at Steady State | AUC at steady state Continuous dosing - AUCss used Intermittent dosing - Weekly AUC used (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Multiple dosing to steady state (up to 12 or 48 hours post dose) | 
| Urine PK - Fraction Dose Excreted (fe(0-12)) Single Dose | Fraction dose excreted unchanged in the urine from 0-12 hours after a single dose (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Pre dose through to 12 hours post dose | 
| Urine PK - Fraction Dose Excreted (fe(0-12)) at Steady State | Fraction dose excreted unchanged in the urine from 0-12 hours after dosing (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Pre dose through to 24 hours post dose | 
| Urine PK - Renal Clearance (Renal CL) Single Dose | Renal Clearance (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Pre dose through to 24 hours post dose | 
| Urine PK - Renal Clearance (Renal CL) at Steady State | Renal Clearance (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered) | Pre dose through to 24 hours post dose | 
| Percent Change From Baseline in p4EBP1 at 2 Hours Post Dose | Phosphorylation levels of 4EBP1 from peripheral blood mononuclear cell (Patients with undetectable values at baseline have been excluded) | predose and 2 hours after a single dose | 
| Percent Change From Baseline in pAKT (S473) in Platelet Rich Plasma (PRP) at 2 Hours Post Dose | Phosphorylation levels of AKT from PRP (Patients with undetectable values at baseline have been excluded) | predose and 2 hours after a single dose | 
| Partial Metabolic Response (PMR), Cycle 1 | Partial metabolic responses measured by 2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) (or FDG-PET/Computed Tomography (CT)) with a comparison to baseline (pre-dose) | Cycle 1 Day 8 | 
| Partial Metabolic Response (PMR), Cycle 2 | Partial metabolic responses measured by 2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) (or FDG-PET/Computed Tomography (CT)) with a comparison to baseline (pre-dose) | Cycle 2 Day 8 | 
| Complete Metabolic Response (CMR), Cycle 1 | Complete metabolic responses measured by 2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) (or FDG-PET/Computed Tomography (CT)) with a comparison to baseline (pre-dose) | Cycle 1 Day 8 | 
| Complete Metabolic Response (CMR), Cycle 2 | Complete metabolic responses measured by 2-[F-18]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) (or FDG-PET/Computed Tomography (CT)) with a comparison to baseline (pre-dose) | Cycle 2 Day 8 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, cancer, advanced solid malignancies, dose escalation, AZD2014, mTor kinase inhibitor, safety, pharmacokinetics