Back to resultsSafety, Tolerability & Potential Anti-cancer Activity of Increasing Doses of AZD5363 in Different Treatment Schedules
Primary Purpose
Advanced Solid Malignancy, Safety and Tolerability, Pharmacokinetics
Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
AZD5363
AZD5363
AZD5363
AZD5363
Sponsored by
About this trial
This is an interventional treatment trial for Advanced Solid Malignancy focused on measuring Advanced solid malignancy,PIK3CA mutated,AKT1 mutated, PTEN mutation, PTEN alteration, metastatic,ER+,breast,ovarian,endometrial,AZD5363,AKT inhibitor,
Eligibility 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.
Sites / Locations
- Research Site
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- Research Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Experimental
Experimental
Experimental
Arm Label
Part A and B Schedule 1, Continuous dosing
Parts A,B,C,D Schedule 2, Intermittent dosing
Parts A and B Schedule 3, Intermittent dosing.
Parts E and F, Intermittent dosing with Fulvestrant
Arm Description
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.
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).
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
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.
Outcomes
Primary Outcome Measures
Parts A,B,C,D,E & F : Safety and tolerability of AZD5363 in terms of adverse events and serious adverse events
Parts A,B,C,D,E & F : Safety and tolerability of AZD5363 in terms of death
Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing changes from baseline of laboratory data (clinical chemistry, haematology, urinalysis)
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
Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing changes from baseline in electrocardiogram (ECG) parameters
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).
Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing left ventricular ejection fraction (LVEF).
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.
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01226316
Brief Title
Safety, Tolerability & Potential Anti-cancer Activity of Increasing Doses of AZD5363 in Different Treatment Schedules
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 1, 2010 (Actual)
Primary Completion Date
April 26, 2019 (Actual)
Study Completion Date
December 31, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
AstraZeneca
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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 Positive, HER2 Positive
Keywords
Advanced solid malignancy,PIK3CA mutated,AKT1 mutated, PTEN mutation, PTEN alteration, metastatic,ER+,breast,ovarian,endometrial,AZD5363,AKT inhibitor,
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
285 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part A and B Schedule 1, Continuous dosing
Arm Type
Experimental
Arm Description
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.
Arm Title
Parts A,B,C,D Schedule 2, Intermittent dosing
Arm Type
Experimental
Arm Description
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).
Arm Title
Parts A and B Schedule 3, Intermittent dosing.
Arm Type
Experimental
Arm Description
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
Arm Title
Parts E and F, Intermittent dosing with Fulvestrant
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
AZD5363
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
AZD5363
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
AZD5363
Intervention Description
Optional additional schedule. Patients will be given AZD5363 administered orally. Regimen to be determined in response to emerging clinical findings.
Intervention Type
Drug
Intervention Name(s)
AZD5363
Intervention Description
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.
Primary Outcome Measure Information:
Title
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.
Title
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
Title
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
Title
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
Title
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.
Title
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.
Title
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
Secondary Outcome Measure Information:
Title
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)
Title
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
130 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gaia Schiavon, MSD
Organizational Affiliation
AstraZeneca
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Udai Banerji, MD, PhD
Organizational Affiliation
Institute of Cancer Research, United Kingdom
Official's Role
Principal Investigator
Facility Information:
Facility Name
Research Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90089
Country
United States
Facility Name
Research Site
City
Stanford
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Research Site
City
West Hollywood
State/Province
California
ZIP/Postal Code
90048
Country
United States
Facility Name
Research Site
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Research Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Research Site
City
New York
State/Province
New York
ZIP/Postal Code
10022
Country
United States
Facility Name
Research Site
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Research Site
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Research Site
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Research Site
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Research Site
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37204
Country
United States
Facility Name
Research Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Research Site
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 1Z2
Country
Canada
Facility Name
Research Site
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 4E6
Country
Canada
Facility Name
Research Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Research Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H4A 3T2
Country
Canada
Facility Name
Research Site
City
København Ø
ZIP/Postal Code
2100
Country
Denmark
Facility Name
Research Site
City
Paris Cedex 5
ZIP/Postal Code
75248
Country
France
Facility Name
Research Site
City
Pierre Benite CEDEX
ZIP/Postal Code
69310
Country
France
Facility Name
Research Site
City
Villejuif
ZIP/Postal Code
94805
Country
France
Facility Name
Research Site
City
Milan
ZIP/Postal Code
20141
Country
Italy
Facility Name
Research Site
City
Napoli
ZIP/Postal Code
80131
Country
Italy
Facility Name
Research Site
City
Prato
ZIP/Postal Code
59100
Country
Italy
Facility Name
Research Site
City
Chuo-ku
ZIP/Postal Code
104-0045
Country
Japan
Facility Name
Research Site
City
Kashiwa
ZIP/Postal Code
277-8577
Country
Japan
Facility Name
Research Site
City
Koto-ku
ZIP/Postal Code
135-8550
Country
Japan
Facility Name
Research Site
City
Sapporo-shi
ZIP/Postal Code
060-8638
Country
Japan
Facility Name
Research Site
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands
Facility Name
Research Site
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Facility Name
Research Site
City
Madrid
ZIP/Postal Code
08035
Country
Spain
Facility Name
Research Site
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Research Site
City
Valencia
ZIP/Postal Code
46010
Country
Spain
Facility Name
Research Site
City
Manchester
ZIP/Postal Code
M20 4BX
Country
United Kingdom
Facility Name
Research Site
City
Sutton
ZIP/Postal Code
SM2 5PT
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.
All request will be evaluated as per the AZ disclosure commitment:
https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
IPD Sharing Time Frame
AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
IPD Sharing Access Criteria
When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
IPD Sharing URL
https://astrazenecagroup-dt.pharmacm.com/DT/Home
Citations:
PubMed Identifier
34250397
Citation
Smyth LM, Reichel JB, Tang J, Patel JAA, Meng F, Selcuklu DS, Houck-Loomis B, You D, Samoila A, Schiavon G, Li BT, Razavi P, Piscuoglio S, Reis-Filho JS, Taylor BS, Baselga J, Solit DB, Hyman DM, Berger MF, Chandarlapaty S. Utility of Serial cfDNA NGS for Prospective Genomic Analysis of Patients on a Phase I Basket Study. JCO Precis Oncol. 2021 Jan 8;5:PO.20.00184. doi: 10.1200/PO.20.00184. eCollection 2021.
Results Reference
derived
PubMed Identifier
33863913
Citation
Smyth LM, Batist G, Meric-Bernstam F, Kabos P, Spanggaard I, Lluch A, Jhaveri K, Varga A, Wong A, Schram AM, Ambrose H, Carr TH, de Bruin EC, Salinas-Souza C, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Nikolaou M, Schiavon G, Razavi P, Banerji U, Baselga J, Hyman DM, Chandarlapaty S. Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer. NPJ Breast Cancer. 2021 Apr 16;7(1):44. doi: 10.1038/s41523-021-00251-7.
Results Reference
derived
PubMed Identifier
32312891
Citation
Smyth LM, Tamura K, Oliveira M, Ciruelos EM, Mayer IA, Sablin MP, Biganzoli L, Ambrose HJ, Ashton J, Barnicle A, Cashell DD, Corcoran C, de Bruin EC, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Pass M, Rowlands V, Schiavon G, Banerji U, Scaltriti M, Taylor BS, Chandarlapaty S, Baselga J, Hyman DM. Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer. Clin Cancer Res. 2020 Aug 1;26(15):3947-3957. doi: 10.1158/1078-0432.CCR-19-3953. Epub 2020 Apr 20.
Results Reference
derived
PubMed Identifier
29066505
Citation
Banerji U, Dean EJ, Perez-Fidalgo JA, Batist G, Bedard PL, You B, Westin SN, Kabos P, Garrett MD, Tall M, Ambrose H, Barrett JC, Carr TH, Cheung SYA, Corcoran C, Cullberg M, Davies BR, de Bruin EC, Elvin P, Foxley A, Lawrence P, Lindemann JPO, Maudsley R, Pass M, Rowlands V, Rugman P, Schiavon G, Yates J, Schellens JHM. A Phase I Open-Label Study to Identify a Dosing Regimen of the Pan-AKT Inhibitor AZD5363 for Evaluation in Solid Tumors and in PIK3CA-Mutated Breast and Gynecologic Cancers. Clin Cancer Res. 2018 May 1;24(9):2050-2059. doi: 10.1158/1078-0432.CCR-17-2260. Epub 2017 Oct 24.
Results Reference
derived
Links:
URL
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Safety, Tolerability & Potential Anti-cancer Activity of Increasing Doses of AZD5363 in Different Treatment Schedules
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