Clinical trial NCT01226316: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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,
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2010-10-22
Enrollment: 285
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Parts A,B,C,D,E & F : Safety and tolerability of AZD5363 in terms of adverse events and serious adverse events
timeFrame: Adverse events, serious adverse events and deaths will be collected from screening to 28 days after study drug discontinuation.
measure: Parts A,B,C,D,E & F : Safety and tolerability of AZD5363 in terms of death
timeFrame: Deaths will be collected from screening to 28 days after study drug discontinuation
measure: Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing changes from baseline of laboratory data (clinical chemistry, haematology, urinalysis)
timeFrame: Laboratory data will be collected from screening to 28 days after study drug discontinuation
measure: 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
timeFrame: Vital signs and ECGs will be recorded from screening to 28 days after study drug discontinuation
measure: Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing changes from baseline in electrocardiogram (ECG) parameters
timeFrame: ECGs will be collected from screening to 28 days after study drug discontinuation.
measure: 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).
timeFrame: Glucose parameters will be collected from screening to 28 days after study discontinuation.
measure: Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing left ventricular ejection fraction (LVEF).
timeFrame: Multiple Gated Acquisition (MUGA) or Echocardiogram assessments to be carried out from screening until study drug discontinuation
Secondary outcomes:
measure: 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.
timeFrame: 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)
measure: 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
timeFrame: Tumour assessment by RECIST at 6,12,18,24wks then at 12 weekly intervals until discontinuation of study therapy
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Stanford
country: United States
facility: Research Site
state: California
city: West Hollywood
country: United States
facility: Research Site
state: California
city: Aurora
country: United States
facility: Research Site
state: Colorado
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Portland
country: United States
facility: Research Site
state: Oregon
city: Charleston
country: United States
facility: Research Site
state: South Carolina
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Nashville
country: United States
facility: Research Site
state: Tennessee
city: Houston
country: United States
facility: Research Site
state: Texas
city: Edmonton
country: Canada
facility: Research Site
state: Alberta
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: København Ø
country: Denmark
facility: Research Site
city: Paris Cedex 5
country: France
facility: Research Site
city: Pierre Benite CEDEX
country: France
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Milan
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Prato
country: Italy
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Kashiwa
country: Japan
facility: Research Site
city: Koto-ku
country: Japan
facility: Research Site
city: Sapporo-shi
country: Japan
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Gaia Schiavon, MSD
role: STUDY_DIRECTOR
affiliation: Institute of Cancer Research, United Kingdom
name: Udai Banerji, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.