Safety, Tolerability & Potential Anti-cancer Activity of Increasing Doses of AZD5363 in Different Treatment Schedules - Full Text View

Purpose

This study is designed to investigate the safety and tolerability of a new drug, AZD5363, in patients with advanced cancer - and to identify a dose and schedule that can be used in the future. This study will also 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. This study will also investigate anti-tumour activity of AZD5363 in patients with advanced / metastatic breast, gynaecological cancers or other solid cancers bearing either AKT1 or PIK3CA mutation.

Condition	Intervention	Phase
Advanced Solid Malignancy Safety and Tolerability Pharmacokinetics Pharmacodynamics Tumour Response Advanced or Metastatic Breast Cancer Ovarian Cancer Cervical Cancer Endometrial Cancer PIK3CA AKT1 ER+ HER2+	Drug: AZD5363	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized 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 Anti-tumour Activity of Ascending Doses of AZD5363 Under Adaptable Dosing Schedules in Patients With Advanced Solid Malignancies.

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Benign Tumors Cancer Cervical Cancer Ovarian Cancer

U.S. FDA Resources

Further study details as provided by AstraZeneca:

Primary Outcome Measures:

Parts A,B,C,D: Safety and tolerability of AZD5363 in terms of adverse events and serious adverse events [ Time Frame: Adverse events, serious adverse events and deaths will be collected from screening to 28 days after study drug discontinuation. ] [ Designated as safety issue: Yes ]
Parts A,B,C,D: Safety and tolerability of AZD5363 in terms of death [ Time Frame: Deaths will be collected from screening to 28 days after study drug discontinuation ] [ Designated as safety issue: Yes ]
Parts A,B,C,D: Safety and tolerability of AZD5363 by assessing changes from baseline of laboratory data (clinical chemistry, haematology, urinalysis) [ Time Frame: Laboratory data will be collected from screening to 28 days after study drug discontinuation ] [ Designated as safety issue: Yes ]
Parts A,B,C,D: Safety and tolerability of AZD5363 in terms of changes from baseline in vital signs and in electrocardiogram (ECG) parameters [ Time Frame: Vital signs and ECGs will be recorded from screening to 28 days after study drug discontinuation ] [ Designated as safety issue: Yes ]
Parts A,B,C,D: Safety and tolerability of AZD5363 by assessing changes from baseline in electrocardiogram (ECG) parameters [ Time Frame: ECGs will be collected from screening to 28 days after study drug discontinuation. ] [ Designated as safety issue: Yes ]
Parts A,B,C,D: Safety and tolerability of AZD5363 by assessing changes from baseline of glucose laboratory parameters (Urine, serum and plasma glucose, glycosylated haemoglobin). [ Time Frame: Glucose parameters will be collected from screening to 28 days after study discontinuation. ] [ Designated as safety issue: Yes ]
Parts A,B,C,D: Safety and tolerability of AZD5363 by assessing left ventricular ejection fraction (LVEF). [ Time Frame: Multiple Gated Acquisition (MUGA) or Echocardiogram assessments to be carried out from screening until study drug discontinuation ] [ Designated as safety issue: Yes ]
Part E: Compare AZD5363 PK exposure of tablet and capsule formulations: Maximum plasma concentration at steady state, time to Cmax, and area under the plasma concentration-time curve at steady state. [ Time Frame: Blood sample taken on Day 4 and 11 (4day on 3day off schedule ) pre-dose, 30min, 1, 2, 4, 6, 8,12h ] [ Designated as safety issue: No ]
Part F: Effect of a meal on PK exposure of a AZD5363 tablet formulation: maximum plasma concentration at steady state, time to Cmax, and area under the plasma concentration-time curve at steady state. [ Time Frame: Blood sample taken Days 1 and 8 (pre-dose only), Days 4 and 11 (pre-dose, 30min, 1, 2, 4, 6, 8,12h) ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To characterise AZD5363 PK following single & multiple dosing by assessment of maximum plasma concentration,time to Cmax, terminal rate constant, terminal half life,area under the plasma concentration-time curve,plasma clearance & volume of distribution. [ Time Frame: Sample:Parts A&B:Cycle0 Day1(pre-dose,30min,1,2,4,6,8,10-12,24&48h post-dose),C1 D1 (pre-dose),D8/Last wkly dose (pre-dose,30min,1,2,4,6,8,10-12h post dose),D15/Last wkly dose+7 (pre-dose),Part C,D:C1 D1(pre-dose)& D15/last wkly dose+7dys (pre-dose,2,4h) ] [ Designated as safety issue: No ]
Parts A,B,C,D, E, F: To obtain a preliminary assessment of anti-tumour activity of AZD5363 via use of Response Evaluation Criteria in Sold Tumours (RECIST) version 1.1 [ Time Frame: Tumour assessment by RECIST at 6 weekly intervals until discontinuation of study therapy ] [ Designated as safety issue: No ]
Parts E,F: Safety and tolerability of AZD5363 in terms of adverse events and serious adverse events, death, changes from baseline of laboratory data (clinical chemistry, haematology, urinalysis), vital signs, and electrocardiogram (ECG) parameters [ Time Frame: Collected from screening to 28 days after study drug discontinuation ] [ Designated as safety issue: Yes ]
Part E: assess multiple dose PK data for AZD5363 new tablet formulation by maximum plasma concentration at steady state, time to Cmax, area under plasma concentration time curve at steady state, oral plasma clearance at steady state [ Time Frame: Blood sample taken on Day 4 and 11 (4day on 3day off schedule) pre-dose, 30min, 1, 2, 4, 6, 8,12h ] [ Designated as safety issue: No ]
Part F: within-patient comparison of steady state exposure of AZD5363 tablet with/without food: plasma concentrations Css max and Css min, time to Css max, area under the plasma concentration-time curve at steady state. [ Time Frame: Blood sample taken Days 1 and 8 (pre-dose only), Days 4 and 11 (pre-dose, 30min, 1, 2, 4, 6, 8,12h) ] [ Designated as safety issue: No ]

Estimated Enrollment:	200
Study Start Date:	November 2010
Estimated Study Completion Date:	December 2016
Estimated Primary Completion Date:	December 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Part A and B Schedule 1, Continuous dosing Part A: Ascending doses of AZD5363 administered orally, every day to define the maximum tolerated dose. Part B: Dose expansion phase, at the defined maximum tolerated dose or recommended dose from Part A.	Drug: AZD5363 Patients will receive a single dose of AZD5363, administered orally, followed by a 3-7 day wash-out period. Patients will then commence with twice-daily dosing, administered orally, every day, to cessation of therapy.
Experimental: Parts A,B,C,D Schedule 2, Intermittent dosing Part A: Ascending doses of AZD5363 administered orally, twice daily, on a 7-day repeating regimen, to define the maximum tolerated dose. Part B: Dose expansion phase, at the defined maximum tolerated dose or recommended dose from Part A. Part C and D:AZD5363 orally, twice daily on an intermittent regimen (4 days on, 3 days off).	Drug: AZD5363 Patients will be given AZD5363 administered orally as a single dose, followed by a 3-7 day wash-out period. Patients will then receive AZD5363 twice daily on 6 or fewer days per weekly regimen, to cessation of therapy. Parts C,D: Oral AZD5363 twice daily, 4 days on treatment, 3 days off treatment, to cessation of therapy.
Experimental: Parts A and B Schedule 3, Intermittent dosing. Part A: Ascending doses of AZD5363 administered orally, twice daily, on an alternative weekly regimen. Initiation of Schedule 3 is dependant on emerging clinical data. Part B: Dose expansion phase, at the defined maximum tolerated dose or recommended dose from Part A	Drug: AZD5363 Optional additional schedule. Patients will be given AZD5363 administered orally. Regimen to be determined in response to emerging clinical findings.
Experimental: Part E Formulation Switch AZD5363 tablet twice daily followed by AZD5363 capsule on an intermittent regimen (4 days on, 3 days off).	Drug: AZD5363 Oral AZD5363 twice daily, 4 days on 3 days off tablet formulation for one week, followed by two weeks with capsule formulation.
Experimental: Part F Food Effect AZD5363 tablet twice daily on an intermittent regimen (4 days on, 3 days off) with/without food on one occasion	Drug: AZD5363 Oral AZD5363 twice daily, 4 days on 3 days off tablet formulation. On day 4 oral AZD5363 tablet without food. On day 11 oral AZD5363 tablet with food

Detailed Description:

A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of Ascending Doses of AZD5363 under Adaptable Dosing Schedules in Patients with Advanced Solid Malignancies.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Aged at least 18 years.
Parts A,B,E,F: The presence of a solid, malignant tumour, excluding lymphoma, that is resistance to standard therapies or for which no standard therapies exist.
ER+/HER2+ breast, ovarian, cervical, endometrial cancer, or other solid cancers, resistance to standard therapies with a PIK3CA gene mutation (Part C), AKT1 gene mutation (Part D) or a dysregulatory aberration on the PIK/AKT pathway (Part D)
The presence of at least one lesion that can be accurately assessed at baseline by CT, MRI or plain X-ray and is suitable for repeated assessment. Estimated life expectancy of more than 12 weeks.
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 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01226316

Contacts

Contact: AstraZeneca Clinical Study Information

800-236-9933

information.center@astrazeneca.com

Locations

Netherlands
Research Site	Recruiting
Amsterdam, Netherlands
United Kingdom
Research Site	Recruiting
Sutton, Surrey, United Kingdom
Research Site	Recruiting
Manchester, United Kingdom

Sponsors and Collaborators

AstraZeneca

Investigators

Study Director:	Paul Stockman, MBChB, PhD	AstraZeneca
Principal Investigator:	Udai Banerji, MD, PhD	Institute of Cancer Research, United Kingdom

More Information

No publications provided

Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT01226316 History of Changes
Other Study ID Numbers:	D3610C00001, EudraCT number: 2010-022167-35
Study First Received:	October 21, 2010
Last Updated:	April 29, 2013
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Federal Institute for Drugs and Medical Devices Spain: Agencia Espanola del Medicamento y Productos Sanitarios (AEMPS) United States: Food and Drug Administration Japan: Pharmaceuticals and Medical Devices Agency

Keywords provided by AstraZeneca:

Advanced solid malignancy,refractory,PIK3CA mutated,AKT1 mutated, metastatic,ER+ HER2+,breast,ovarian,endometrial,AZD5363,food effect,formulation comparison

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasms
Endometrial Neoplasms
Uterine Cervical Neoplasms
Ovarian Neoplasms
Adenoma
Neoplasms by Site
Breast Diseases
Skin Diseases
Uterine Neoplasms
Genital Neoplasms, Female

Urogenital Neoplasms
Uterine Diseases
Genital Diseases, Female
Uterine Cervical Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Endocrine System Diseases
Gonadal Disorders
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on May 19, 2013