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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01625286
First received: May 10, 2012
Last updated: September 15, 2014
Last verified: September 2014
  Purpose

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.


Condition Intervention Phase
Advanced or Metastatic Breast Cancer,
ER+ve Advanced or Metastatic Breast Cancer.
Drug: AZD5363 when combined with weekly paclitaxel.
Drug: AZD5363when combined with weekly paclitaxel.
Drug: A placebo in combination with weekly paclitaxel.
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of AZD5363 Combined With Paclitaxel in Patients With Advanced or Metastatic Breast Cancer. Comprising a Safety Run-In and a Placebo-controlled Randomised Expansion in ER+ve Patients Stratified by PIK3CA Mutation Status.

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Part A: Safety and tolerability of AZD5363 when combined with paclitaxel, in terms of numbers of patients with adverse events and serious adverse events. [ Time Frame: Adverse events and toxicities recorded from patient screening to first of: date of withdrawal from study, date of death or date of patient completion of study. Average participation approximately 18 weeks. ] [ Designated as safety issue: Yes ]
  • Part B: Relative efficacy of AZD5363, compared to placebo, when combined with paclitaxel, by assessment of progression-free survival. [ Time Frame: Tumour assessments by RECIST at screening and at 12 weekly intervals until first of: date of first documented progression, date of study withdrawal or date of death. Average participation approximately 18 weeks. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Part A: Preliminary anti-tumour activity of AZD5363 when combined with paclitaxel, by assessment of overall response rate (ORR) and percentage of patients without progressive disease at 12 weeks. [ Time Frame: Tumour assessment by RECIST at patient screening and at 12 weeks after date of start of study therapy. ] [ Designated as safety issue: No ]
  • Part B: Relative efficacy of AZD5363, compared to placebo, when combined with paclitaxel, by assessment of ORR at 12 weeks, best objective response (BOR) and durable response rate (DDR). [ Time Frame: Tumour assessment by RECIST at patient screening and at 12 weeks after date of start of study therapy (ORR) and first of: date of first documented progression, date of study withdrawal or date of death. Average participation approximately 18 weeks. ] [ Designated as safety issue: No ]
  • Part B: Relative anti-tumour activity of AZD5363, compared to placebo, when combined with paclitaxel, by comparison of change in tumouir size at 12 weeks. [ Time Frame: Tumour assessment by RECIST at screening and at 12 weeks after date of start of study therapy. ] [ Designated as safety issue: No ]
  • Part B: Safety and tolerability of AZD5363 when combined with paclitaxel,in terms of numbers of patients with adverse events and serious adverse events. [ Time Frame: Adverse events and toxicities recorded from patient screening to first of: date of study withdrawal, date of death or 28 days after date of discontinuation of all study therapies. Average participation approximately 24 weeks. ] [ Designated as safety issue: Yes ]
  • Part B: Effect on patient's quality of life (QoL) due to receipt of AZD5363 when combined with paclitaxel, by assessing changes from baseline score in a patient-completed QoL questionnaire (EORTC QLQ-30 / BR-23). [ Time Frame: QoL questionnaires completed at screening and at 12 weekly intervals from screening until first of: date of study withdrawal, date of death or date of discontinuation of all study therapies. Average participation approximately 24 weeks. ] [ Designated as safety issue: No ]
  • Parts A and B: Assessment of the plasma concentration profile of AZD5363 when combined with paclitaxel. [ Time Frame: AZD5363 plasma concentration samples will be collected during the first treatment cycle on: Part A days 2, 3, 5, 9, 16 and 23, and Part B days 2, 9 and 16, from date of start of study therapy. ] [ Designated as safety issue: No ]
  • Parts A and B: Assessment of the plasma concentration (PK) profile of paclitaxel alone and when combined with AZD5363. [ Time Frame: Paclitaxel plasma concentration samples will be collected during the first treatment cycle on: Part A days 1, 2, 9, and 16, and Part B days 1 and 2, from date of start of study therapy. ] [ Designated as safety issue: No ]
  • Parts A and B: Assessment of the pharmacokinetic/pharmacodynamic relationship between plasma concentration of AZD5363 and plasma concentrations of pharmacodynamic biomarkers and correlation with anti-tumour activity. [ Time Frame: PD samples will be collected on:Part A days 1,2,3,5,9,16,23; Part B days 1,2,16 from therapy start & day 1 of each cycle. PK sampling & anti-tumour activity assessment timepoints are as decribed previously. Average participation approximately 18 weeks. ] [ Designated as safety issue: No ]
  • Part B: Overall survival of patients treated with AZD5363, compared to placebo, when in combination with paclitaxel by assessment of time to death. [ Time Frame: First of: date of study withdrawal or date of death. Average participation approximately 52 weeks. ] [ Designated as safety issue: No ]

Estimated Enrollment: 160
Study Start Date: October 2012
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part A: Intermittent schedule (2/5)
See intervention description below.
Drug: AZD5363 when combined with weekly paclitaxel.
AZD5363: oral capsule, twice daily in a weekly 2 days on-treatment, 5 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
Experimental: Part A: Intermittent schedule (4/3)
See intervention description below.
Drug: AZD5363 when combined with weekly paclitaxel.
AZD5363: oral capsule, twice daily in a weekly 4 days on-treatment, 3 days-off, schedule. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
Active Comparator: Part B: AZD5363 combined with paclitaxel
See intervention description below.
Drug: AZD5363when combined with weekly paclitaxel.
Either a 2/5 or 3/4 intermittent dosing schedule of AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
Placebo Comparator: Part B: paclitaxel combined with placebo
See intervention description below.
Drug: A placebo in combination with weekly paclitaxel.
Either a 2/5 or 3/4 intermittent dosing schedule of placebo matched to AZD5363 based on the outcome of Part A. Dosage: oral formulation, twice daily. Treatment to begin the day following the first dose of paclitaxel and to continue until treatment withdrawal. Paclitaxel: intravenously once a week. placebo and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01625286

Contacts
Contact: AstraZeneca Clinical Study Information 800-236-9933 ClinicalTrialTransparency@astrazeneca.com

Locations
Bulgaria
Research Site Not yet recruiting
Plovdiv, Bulgaria
Research Site Not yet recruiting
Sofia, Bulgaria
France
Research Site Recruiting
Paris Cedex 5, France
Research Site Recruiting
Pierre Benite Cedex, France
Research Site Recruiting
Villejuif, France
Japan
Research Site Recruiting
Chuo-ku, Japan
Research Site Recruiting
Fukuoka-shi, Japan
Research Site Not yet recruiting
Osaka-shi, Japan
Mexico
Research Site Not yet recruiting
Estado de México, Mexico
Research Site Not yet recruiting
Juchitan, Mexico
Research Site Not yet recruiting
Merida, Mexico
Research Site Not yet recruiting
Monterrey, Mexico
Research Site Not yet recruiting
Oaxaca de Juarez, Mexico
Netherlands
Research Site Withdrawn
Amsterdam, Netherlands
Peru
Research Site Not yet recruiting
Lima, Peru
Spain
Research Site Recruiting
Barcelona, Spain
Research Site Recruiting
Madrid, Spain
Research Site Recruiting
Valencia, Spain
United Kingdom
Research Site Recruiting
London, United Kingdom
Research Site Recruiting
Manchester, United Kingdom
Research Site Recruiting
Sutton, United Kingdom
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Justin Lindemann, MBChB MBA AstraZeneca
  More Information

No publications provided

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01625286     History of Changes
Other Study ID Numbers: D3610C00002, 2011-006312-31
Study First Received: May 10, 2012
Last Updated: September 15, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Spain: Agencia Española de Medicamentos y Productos Sanitarios

Keywords provided by AstraZeneca:
advanced breast cancer,
metastatic breast cancer,
ER+ve breast cancer,
Estrogen receptor positive breast cancer,
PIK3CA mutated advanced or metastatic breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014