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

• Sponsor: AstraZeneca (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01226316
• Collaborator: (none)
• Enrollment: 285
• Locations: 34
• Arms: 4
• Anticipated Duration (Months): 145
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.1

Study Details

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; Drug: AZD5363; Drug: AZD5363; 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

• Study Type: Interventional
• 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: Dec 1, 2010
• Actual Primary Completion Date: Apr 26, 2019
• Anticipated Study Completion Date: Dec 30, 2022

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

1. Parts A,B,C,D,E & F : Safety and tolerability of AZD5363 in terms of adverse events and serious adverse events [Adverse events, serious adverse events and deaths will be collected from screening to 28 days after study drug discontinuation.]

2. Parts A,B,C,D,E & F : Safety and tolerability of AZD5363 in terms of death [Deaths will be collected from screening to 28 days after study drug discontinuation]

3. Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing changes from baseline of laboratory data (clinical chemistry, haematology, urinalysis) [Laboratory data will be collected from screening to 28 days after study drug discontinuation]

4. 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 [Vital signs and ECGs will be recorded from screening to 28 days after study drug discontinuation]

5. Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing changes from baseline in electrocardiogram (ECG) parameters [ECGs will be collected from screening to 28 days after study drug discontinuation.]

6. 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). [Glucose parameters will be collected from screening to 28 days after study discontinuation.]

7. Parts A,B,C,D,E & F: Safety and tolerability of AZD5363 by assessing left ventricular ejection fraction (LVEF). [Multiple Gated Acquisition (MUGA) or Echocardiogram assessments to be carried out from screening until study drug discontinuation]

Secondary Outcome Measures

1. 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. [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)]

2. 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 [Tumour assessment by RECIST at 6,12,18,24wks then at 12 weekly intervals until discontinuation of study therapy]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Los Angeles	California	United States	90033
2	Research Site	Stanford	California	United States	94304
3	Research Site	West Hollywood	California	United States	90048
4	Research Site	Aurora	Colorado	United States	80045
5	Research Site	Boston	Massachusetts	United States	02215
6	Research Site	New York	New York	United States	10022
7	Research Site	Oklahoma City	Oklahoma	United States	73104
8	Research Site	Portland	Oregon	United States	97239
9	Research Site	Charleston	South Carolina	United States	29425
10	Research Site	Nashville	Tennessee	United States	37203
11	Research Site	Nashville	Tennessee	United States	37204
12	Research Site	Houston	Texas	United States	77030
13	Research Site	Edmonton	Alberta	Canada	T6G 1Z2
14	Research Site	Vancouver	British Columbia	Canada	V5Z 4E6
15	Research Site	Toronto	Ontario	Canada	M5G 2M9
16	Research Site	Montreal	Quebec	Canada	H4A 3T2
17	Research Site	København Ø		Denmark	2100
18	Research Site	Paris Cedex 5		France	75248
19	Research Site	Pierre Benite CEDEX		France	69310
20	Research Site	Villejuif		France	94805
21	Research Site	Milan		Italy	20141
22	Research Site	Napoli		Italy	80131
23	Research Site	Prato		Italy	59100
24	Research Site	Chuo-ku		Japan	104-0045
25	Research Site	Kashiwa		Japan	277-8577
26	Research Site	Koto-ku		Japan	135-8550
27	Research Site	Sapporo-shi		Japan	060-8638
28	Research Site	Amsterdam		Netherlands	1066 CX
29	Research Site	Singapore		Singapore	119228
30	Research Site	Barcelona		Spain	08035
31	Research Site	Madrid		Spain	28041
32	Research Site	Valencia		Spain	46010
33	Research Site	Manchester		United Kingdom	M20 4BX
34	Research Site	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• AstraZeneca

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01226316
• Other Study ID Numbers: D3610C00001; EudraCT number: 2010-022167-35
• First Posted: Oct 22, 2010
• Last Update Posted: Jun 23, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• 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; Endometrial Neoplasms

Study Results

No Results Posted as of Jun 23, 2022