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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01625286
Recruitment Status : Active, not recruiting
First Posted : June 21, 2012
Results First Posted : April 1, 2019
Last Update Posted : September 22, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
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 or disease Intervention/treatment 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

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 148 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, 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
Actual Study Start Date : October 3, 2012
Actual Primary Completion Date : January 28, 2017
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Paclitaxel

Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. Dose-limiting Toxicity (DLT) Events - Part A [ Time Frame: During Part A DLT evaluation period (Cycle 1, up to 28 days) ]
    An Adverse Event (AE) or laboratory abnormality considered to be related to study drug, that starts at any time during the DLT evaluation period (Cycle 1) and is dose limiting

  2. Progression Free Survival (PFS) - Part B [ Time Frame: From randomisation date to date of objective disease progression or death (by any cause) whichever came first, assessed every 12 wks (median total treatment duration AZD5363=325.5 days; Placebo=245 days) ]
    Time from randomisation to date of objective disease progression or death (by any cause in the absence of progression). Progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a >= 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on the study, and an absolute increase of >=5mm, or progression of non-target lesions or the appearance of new lesions.


Secondary Outcome Measures :
  1. Change in Tumour Size at 12 Weeks [ Time Frame: RECIST tumour assessments every 12 weeks ]
    Percentage change from baseline to week 12 in sum of longest diameters of target lesions as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1). Based on patients with measurable disease who had sufficient data available to either calculate or impute a change at 12 weeks

  2. Objective Response Rate (ORR) at Week 12 [ Time Frame: RECIST tumour assessments every 12 weeks ]
    Percentage of patients who have at least one visit response of Complete Response or Partial Response prior to any evidence of progression at week 12 as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm; Objective Response Rate (ORR) = CR + PR

  3. Best Objective Response (BOR) [ Time Frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). ]
    Number of patients, taking their BOR, which is their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.

  4. Overall Objective Response Rate [ Time Frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). ]
    Percentage of patients, taking their best objective tumour response based on RECIST measurements throughout the whole study as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm. Overall Response Rate (ORR) = CR + PR

  5. Number of Subjects Without Progression Disease at Week 12 - Part A [ Time Frame: up to 12 weeks ]
    Percentage of patients with a 12 week visit response of CR, PR or SD (as defined by RECIST 1.1) with no evidence of previous progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.

  6. Duration of Response (DOR) - Part B [ Time Frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). ]
    Date of first documentation of response (Complete Response/Partial Response) until the date of disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Complete Response (CR), disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.. If a subject does not progress following a response, then their DOR will use the PFS censoring time.

  7. Durable Response Rate (DRR) - Part B [ Time Frame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). ]
    Percentage of patients who have a Complete Response (CR) or Partial Response (PR) lasting continuously for at least 24 weeks as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) for target lesions (TL) and assessed by MRI or CT: PR, >=30% decrease in the sum of the longest diameter of target lesions; CR, disappearance of all target lesions, any pathological lymph nodes selected as TLs must have a reduction in short axis to <10mm.

  8. Overall Survival - Part B [ Time Frame: From date of randomisation, assessed every 12 weeks, up until the time of final statistical analysis. (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days). ]
    The interval between the date of randomisation and the date of patient death due to any cause. All Part B patients were analysed, number of deaths is presented.



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01625286


Locations
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Bulgaria
Research Site
Plovdiv, Bulgaria, 4004
Research Site
Sofia, Bulgaria, 1330
Canada, Alberta
Research Site
Calgary, Alberta, Canada, T2N 4N2
Canada, Ontario
Research Site
Ottawa, Ontario, Canada, K1H 8L6
Canada, Quebec
Research Site
Montreal, Quebec, Canada, H4A 3T2
Canada
Research Site
Quebec, Canada, G1S 4L8
Czechia
Research Site
Brno, Czechia, 656 53
France
Research Site
Paris Cedex 5, France, 75248
Research Site
Pierre Benite Cedex, France, 69310
Research Site
Villejuif, France, 94805
Japan
Research Site
Chiba-shi, Japan, 260-8717
Research Site
Chuo-ku, Japan, 104-0045
Research Site
Fukuoka-shi, Japan, 811-1395
Research Site
Mitaka-shi, Japan, 181-8611
Research Site
Oita-shi, Japan, 870-0854
Research Site
Osaka-shi, Japan, 540-0006
Korea, Republic of
Research Site
Seongnam-si, Korea, Republic of, 13620
Research Site
Seoul, Korea, Republic of, 03080
Research Site
Seoul, Korea, Republic of, 03722
Research Site
Seoul, Korea, Republic of, 135-710
Mexico
Research Site
Estado de México, Mexico, 50080
Research Site
Juchitan, Mexico, 7000
Research Site
Monterrey, Mexico, 64460
Research Site
Oaxaca, Mexico, 68000
Peru
Research Site
Lima, Peru, 15036
Research Site
Lima, Peru, L 41
Research Site
Lima, Peru, LIMA 27
Research Site
Miraflores, Peru, 15046
Singapore
Research Site
Singapore, Singapore, 119228
Spain
Research Site
Barcelona, Spain, 08025
Research Site
Barcelona, Spain, 08035
Research Site
Madrid, Spain, 28040
Research Site
Madrid, Spain, 28041
Research Site
Malaga, Spain, 29010
Research Site
Valencia, Spain, 46010
United Kingdom
Research Site
Glasgow, United Kingdom, G12 0YN
Research Site
Leicester, United Kingdom, LE1 5WW
Research Site
London, United Kingdom, SW3 6JJ
Research Site
Manchester, United Kingdom, M20 4BX
Research Site
Plymouth, United Kingdom, PL6 8DH.
Research Site
Sutton, United Kingdom, SM2 5PT
Sponsors and Collaborators
AstraZeneca
Investigators
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Study Director: Justin Lindemann, MBChB MBA AstraZeneca
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol  [PDF] May 30, 2017
Statistical Analysis Plan  [PDF] March 2, 2017

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01625286    
Other Study ID Numbers: D3610C00002
2011-006312-31 ( EudraCT Number )
First Posted: June 21, 2012    Key Record Dates
Results First Posted: April 1, 2019
Last Update Posted: September 22, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
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
AKT inhibitor
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action