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

AstraZeneca172 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

172

Conditions

Advanced Solid Malignancies

Interventions

AZD2014DRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 150 Years

Medical Language ↔ Plain English

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

Locations (2)

Research Site

Manchester, United Kingdom

Research Site

Sutton, United Kingdom

Outcomes

Primary Outcomes

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

Time frame: Up to 21 days from first multiple dose

Secondary Outcomes

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

Time frame: 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)

Time frame: 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)

Data from ClinicalTrials.gov

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Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: Pre dose through to 24 hours post dose

Urine PK - Renal Clearance (Renal CL) at Steady State

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: Cycle 2 Day 8