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

AstraZeneca

Status and phase: Completed; Phase 1

Conditions: PIK3CA; Tumour Response; HER2 Positive; PTEN; Ovarian Cancer; Safety and Tolerability; Endometrial Cancer; Advanced or Metastatic Breast Cancer; ER Positive; Pharmacodynamics; AKT1; Cervical Cancer; Pharmacokinetics; Advanced Solid Malignancy

Treatments: Drug: AZD5363

Study type: Interventional

Funder types: Industry

Identifiers

NCT01226316

D3610C00001

EudraCT number: 2010-022167-35

2010-022167-35 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 285 patients

Sex: All

Ages: 18 to 130 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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285 participants in 4 patient groups

Part A and B Schedule 1, Continuous dosing

Experimental group

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.

Treatment:

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363

Parts A,B,C,D Schedule 2, Intermittent dosing

Experimental group

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).

Treatment:

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363

Parts A and B Schedule 3, Intermittent dosing.

Experimental group

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

Treatment:

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363

Parts E and F, Intermittent dosing with Fulvestrant

Experimental group

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.

Treatment:

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363

Drug: AZD5363