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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01026402
First received: December 3, 2009
Last updated: January 13, 2016
Last verified: January 2016
  Purpose
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.

Condition Intervention Phase
Advanced Solid Malignancies
Drug: AZD2014
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Up to 21 days from first multiple dose ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • Best Objective Response [ Time Frame: Assessed every 8 weeks until progression or withdrawal, whichever came first, estimated to be up to 4 months ] [ Designated as safety issue: No ]
    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

  • Maximum Concentration (Cmax) Single Dose [ Time Frame: Following Single Dose up to 12, 24 or 48 hours post dose ] [ Designated as safety issue: Yes ]
    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)

  • Area Under the Curve (AUC) Single Dose [ Time Frame: Following Single Dose up to 12, 24 or 48 hours post dose ] [ Designated as safety issue: Yes ]
    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)

  • Maximum Concentration (Cmax) at Steady State [ Time Frame: Multiple dosing to steady state (up to 12 or 48 hours post dose) ] [ Designated as safety issue: Yes ]
    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)

  • Area Under the Curve (AUC) at Steady State [ Time Frame: Multiple dosing to steady state (up to 12 or 48 hours post dose) ] [ Designated as safety issue: Yes ]
    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)

  • Urine PK - Fraction Dose Excreted (fe(0-12)) Single Dose [ Time Frame: Pre dose through to 12 hours post dose ] [ Designated as safety issue: Yes ]
    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)

  • Urine PK - Fraction Dose Excreted (fe(0-12)) at Steady State [ Time Frame: Pre dose through to 24 hours post dose ] [ Designated as safety issue: Yes ]
    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)

  • Urine PK - Renal Clearance (Renal CL) Single Dose [ Time Frame: Pre dose through to 24 hours post dose ] [ Designated as safety issue: Yes ]
    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)

  • Urine PK - Renal Clearance (Renal CL) at Steady State [ Time Frame: Pre dose through to 24 hours post dose ] [ Designated as safety issue: Yes ]
    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)

  • Percent Change From Baseline in p4EBP1 at 2 Hours Post Dose [ Time Frame: predose and 2 hours after a single dose ] [ Designated as safety issue: No ]
    Phosphorylation levels of 4EBP1 from peripheral blood mononuclear cell (Patients with undetectable values at baseline have been excluded)

  • Percent Change From Baseline in pAKT (S473) in Platelet Rich Plasma (PRP) at 2 Hours Post Dose [ Time Frame: predose and 2 hours after a single dose ] [ Designated as safety issue: No ]
    Phosphorylation levels of AKT from PRP (Patients with undetectable values at baseline have been excluded)

  • Partial Metabolic Response (PMR), Cycle 1 [ Time Frame: Cycle 1 Day 8 ] [ Designated as safety issue: No ]
    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)

  • Partial Metabolic Response (PMR), Cycle 2 [ Time Frame: Cycle 2 Day 8 ] [ Designated as safety issue: No ]
    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)

  • Complete Metabolic Response (CMR), Cycle 1 [ Time Frame: Cycle 1 Day 8 ] [ Designated as safety issue: No ]
    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)

  • Complete Metabolic Response (CMR), Cycle 2 [ Time Frame: Cycle 2 Day 8 ] [ Designated as safety issue: No ]
    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)


Enrollment: 172
Study Start Date: December 2009
Study Completion Date: August 2014
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AZD2014
AZD2014 dose escalation phase in Part A and expansion phase in Part B.
Drug: AZD2014
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

Ages Eligible for Study:   18 Years to 150 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01026402

Locations
United Kingdom
Research Site
Manchester, United Kingdom
Research Site
Sutton, United Kingdom
Sponsors and Collaborators
AstraZeneca
Investigators
Principal Investigator: Dr. Udai Banerji The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT
Study Director: Elisabeth Oelmann AstraZeneca
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01026402     History of Changes
Other Study ID Numbers: D2270C00001  2009-015244-42 
Study First Received: December 3, 2009
Results First Received: October 30, 2015
Last Updated: January 13, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by AstraZeneca:
Phase I
cancer
advanced solid malignancies
dose escalation
AZD2014
mTor kinase inhibitor
safety
pharmacokinetics

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on May 24, 2016