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

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ClinicalTrials.gov Identifier: NCT01226316

Recruitment Status : Active, not recruiting

First Posted : October 22, 2010

Last Update Posted : December 23, 2022

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

AstraZeneca

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.

Condition or disease	Intervention/treatment	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 Positive HER2 Positive	Drug: AZD5363	Phase 1

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	285 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (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
Actual Study Start Date :	December 1, 2010
Actual Primary Completion Date :	April 26, 2019
Estimated Study Completion Date :	December 29, 2023

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Ovarian Cancer Ovarian Epithelial Cancer

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

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. ]
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 ]
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 ]
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 ]
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. ]
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. ]
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 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) ]
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 ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 130 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01226316

Locations

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United States, California
Research Site
Los Angeles, California, United States, 90089
Research Site
Stanford, California, United States, 94304
Research Site
West Hollywood, California, United States, 90048
United States, Colorado
Research Site
Aurora, Colorado, United States, 80045
United States, Massachusetts
Research Site
Boston, Massachusetts, United States, 02215
United States, New York
Research Site
New York, New York, United States, 10022
United States, Oklahoma
Research Site
Oklahoma City, Oklahoma, United States, 73104
United States, Oregon
Research Site
Portland, Oregon, United States, 97239
United States, South Carolina
Research Site
Charleston, South Carolina, United States, 29425
United States, Tennessee
Research Site
Nashville, Tennessee, United States, 37203
Research Site
Nashville, Tennessee, United States, 37204
United States, Texas
Research Site
Houston, Texas, United States, 77030
Canada, Alberta
Research Site
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
Research Site
Vancouver, British Columbia, Canada, V5Z 4E6
Canada, Ontario
Research Site
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Research Site
Montreal, Quebec, Canada, H4A 3T2
Denmark
Research Site
København Ø, Denmark, 2100
France
Research Site
Paris Cedex 5, France, 75248
Research Site
Pierre Benite CEDEX, France, 69310
Research Site
Villejuif, France, 94805
Italy
Research Site
Milan, Italy, 20141
Research Site
Napoli, Italy, 80131
Research Site
Prato, Italy, 59100
Japan
Research Site
Chuo-ku, Japan, 104-0045
Research Site
Kashiwa, Japan, 277-8577
Research Site
Koto-ku, Japan, 135-8550
Research Site
Sapporo-shi, Japan, 060-8638
Netherlands
Research Site
Amsterdam, Netherlands, 1066 CX
Singapore
Research Site
Singapore, Singapore, 119228
Spain
Research Site
Madrid, Spain, 08035
Research Site
Madrid, Spain, 28041
Research Site
Valencia, Spain, 46010
United Kingdom
Research Site
Manchester, United Kingdom, M20 4BX
Research Site
Sutton, United Kingdom, SM2 5PT

Sponsors and Collaborators

AstraZeneca

Investigators

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Study Director:	Gaia Schiavon, MSD	AstraZeneca
Principal Investigator:	Udai Banerji, MD, PhD	Institute of Cancer Research, United Kingdom

More Information

Additional Information:

Related Info This link exits the ClinicalTrials.gov site

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

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.

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Responsible Party:	AstraZeneca
ClinicalTrials.gov Identifier:	NCT01226316
Other Study ID Numbers:	D3610C00001 EudraCT number: 2010-022167-35
First Posted:	October 22, 2010 Key Record Dates
Last Update Posted:	December 23, 2022
Last Verified:	December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
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.
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
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
URL:	https://astrazenecagroup-dt.pharmacm.com/DT/Home

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:

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Neoplasms Endometrial Neoplasms Neoplasms by Site Genital Neoplasms, Female	Urogenital Neoplasms Uterine Neoplasms Uterine Diseases

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