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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01226316
First received: October 21, 2010
Last updated: August 10, 2016
Last verified: August 2016
  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). 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 / PIK3CA or PTEN 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
PTEN
ER+
HER2+
Drug: AZD5363
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel 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:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Parts A,B,C,D,E & F : 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,E & F : 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,E & F: 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,E & F: 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,E & F: 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,E & F: 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,E & F: 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 ]

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:Part A&B:Cycle0Day1(predose,30min,1,2,4,6,8,10-12,24&48h postdose),C1D1(predose),D8/Last wkly dose(predose,30min,1,2,4,6,8,10-12h postdose),D15/Last wkly dose+7(predose),Part C,D,E&F:C1D1(predose,2,4h postdose)&D11(predose,2,4h postdose) ] [ 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 Solid Tumours (RECIST) version 1.1 [ Time Frame: Tumour assessment by RECIST at 6,12,18,24wks then at 12 weekly intervals until discontinuation of study therapy ] [ Designated as safety issue: No ]

Estimated Enrollment: 300
Study Start Date: December 2010
Estimated Study Completion Date: April 2018
Estimated Primary Completion Date: September 2017 (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 (4 days on, 3 days off and 2 days on, 5 days off), to define the maximum tolerated dose. Part B: Dose expansion phase, at the defined maximum tolerated dose or recommended dose from Part A (4 days on, 3 days off and 2 days on, 5 days off). 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: Parts E and F, Intermittent dosing with Fulvestrant
Oral AZD5363 twice daily, 4 days on treatment, 3 days off treatment to cessation of therapy combined with background therapy of fulvestrant at its licensed dose of 500mg intramuscularly on days 1,15,29 and once monthly thereafter to cessation of therapy.
Drug: AZD5363
Patients will receive oral AZD5363 twice daily (4 days on 3 days off treatment)combined with background therapy of fulvestrant at licensed dose of 500mg intramuscularly on days 1,15,29 and once monthly thereafter.

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 to 130 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Aged at least 18 years.
  • Parts A,B: 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), advanced or metastatic ER+ positive breast cancer that has an AKT1 gene mutation (Part E) or advanced or metastatic ER+ positive breast cancer that has a PTEN gene mutation (Part F).
  • 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
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: NCT01226316

Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: Cancer Study Locator 877 400 4656 AstraZeneca@emergingmed.com

  Show 38 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Justin Lindemann, MSD AstraZeneca
Principal Investigator: Udai Banerji, MD, PhD Institute of Cancer Research, United Kingdom
  More Information

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: August 10, 2016
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
Singapore: Health Sciences Authority
Sweden: Medical Products Agency
Italy: Agenzia Italiana del Famaco (AIFA)
Canada: Health Canada

Keywords provided by AstraZeneca:
Advanced solid malignancy,PIK3CA mutated,AKT1 mutated, PTEN mutation, PTEN alteration, metastatic,ER+,breast,ovarian,endometrial,AZD5363,AKT inhibitor,

Additional relevant MeSH terms:
Neoplasms
Uterine Cervical Neoplasms
Endometrial Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Fulvestrant
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 28, 2016