Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients (BEECH)

AstraZeneca

Status and phase: Completed; Phase 2; Phase 1

Conditions: Advanced or Metastatic Breast Cancer; ER+ve Advanced or Metastatic Breast Cancer

Treatments: Drug: A placebo in combination with weekly paclitaxel.; Drug: AZD5363 when combined with weekly paclitaxel.; Drug: AZD5363when combined with weekly paclitaxel.

Study type: Interventional

Funder types: Industry

Identifiers

NCT01625286

D3610C00002

2011-006312-31 (EudraCT Number)

Details and patient eligibility

About

The purpose of this study is to investigate the safety and efficacy of different doses and schedules of AZD5363, when in combination with paclitaxel, in treatment of patients with advanced or metastatic breast cancer. Also to investigate a selected dose and schedule of AZD5363 in combination with paclitaxel vs. paclitaxel in combination with placebo in treatment of patients with estrogen receptor-positive advanced or metastatic breast cancer, including a subgroup who have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) tumour mutation.

Full description

This is a Phase I/II multicentre, study investigating the safety, tolerability and efficacy of a twice-daily oral formulation of AZD5363 when combined with a weekly intravenous paclitaxel infusion in patients with advanced or metastatic breast cancer. Study treatment is given in 28-day cycles, comprising three weeks on-therapy followed by one week off-therapy.

The study will be conducted in two parts:

Part A. Approximately 40 patients will be recruited to this Phase I multiple ascending-dose safety run-in evaluation of each of two intermittent dosing schedules (2 days per week or 4 days per week) of AZD5363 given in combination with weekly paclitaxel. The study population is female patients, 18 years or older, with advanced or metastatic breast cancer.

The purpose of Part A is to assess the comparative safety, tolerability, pharmacokinetics and preliminary efficacy of both schedules to determine one dose and schedule of AZD5363 to take forward to study Part B in combination with weekly paclitaxel.

Part A assessments will be made in dose-escalating cohorts of 3 to 6 patients to determine a recommended dose in each of the schedules. A total of 6 patients must be evaluated at a selected dose level for it to be confirmed as the recommended dose. All dose evaluations and recommendations will be conducted by a Safety Review Committee.

Part A Patients will undergo assessments up to to withdrawal from the study or to discontinuation of study therapy.

Part B. A minimum of 100 patients will be recruited to this Phase II double-blind, placebo-controlled, stratified and randomised evaluation of two treatment regimens: AZD5363 (at a dose selected and schedule from Part A) in combination with weekly paclitaxel vs. weekly paclitaxel plus placebo. The study population is female patients with Estrogen Receptor Positive advanced or metastatic breast cancer; of which approximately 50 will have the phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) mutation.

Part B patients will be stratified by PIK3CA tumour mutation status as: tumour mutation positive or tumour mutation not-detected. Under each stratum patients will be randomised to receive either paclitaxel + AZD5363 or paclitaxel + placebo.

The purpose of Part B is to assess relative efficacy of both active and placebo regimens by comparison of: progression-free survival, overall survival, tumour response, safety and tolerability in the overall ER+ve advanced or metastatic breast cancer population, and in a subgroup of these patients with the PIK3CA tumour mutation. Patient safety and therapy tolerability will be monitored by an independent Safety Review Committee throuighout the course of Part B.

Part B patients will be followed for assessment of overall survival, or to withdrawal from the study.

Enrollment: 148 patients

Sex: Female

Ages: 18 to 130 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Provision of informed consent.
• Female patient.
• Aged at least 18 years.
• Histological or cytological confirmation of breast cancer with evidence of advanced or metastatic disease (must be ER+ve, HER2-ve, in Part B).
• World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 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.
• Any prior exposure to agents which inhibit AKT as the primary pharmacological activity.
• Part A: more than two prior courses of chemotherapy (including taxanes) for advanced or metastatic breast cancer.

Part B: any prior chemotherapy for advanced or metastatic breast cancer.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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148 participants in 4 patient groups, including a placebo group

Part A: Intermittent schedule (2/5)

Experimental group

Description:

See intervention description below.

Treatment:

Drug: AZD5363 when combined with weekly paclitaxel.

Drug: AZD5363 when combined with weekly paclitaxel.

Part A: Intermittent schedule (4/3)

Experimental group

Description:

See intervention description below.

Treatment:

Drug: AZD5363 when combined with weekly paclitaxel.

Drug: AZD5363 when combined with weekly paclitaxel.

Part B: AZD5363 combined with paclitaxel

Active Comparator group

Description:

See intervention description below.

Treatment:

Drug: AZD5363when combined with weekly paclitaxel.

Part B: paclitaxel combined with placebo

Placebo Comparator group

Description:

See intervention description below.

Treatment:

Drug: A placebo in combination with weekly paclitaxel.