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

• ClinicalTrials.gov Identifier: NCT01625286
• Recruitment Status: Completed
• First Posted: June 21, 2012
• Results First Posted: April 1, 2019
• Last Update Posted: January 18, 2023
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

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.

Study Design

• 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
• Actual Study Completion Date: October 3, 2022

Arms and Interventions

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.

Outcome Measures

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.

Eligibility Criteria

• 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.

Contacts and Locations

Locations

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

Madrid, 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

• Study Director: Justin Lindemann, MBChB MBA; AstraZeneca

  Study Documents (Full-Text)

Documents provided by AstraZeneca:

Study Protocol  [PDF] February 24, 2012

Statistical Analysis Plan  [PDF] March 2, 2017

More Information

Additional Information:

CSPandAmendments_redacted 

SAP_PartAandB_redactedsignature 

SAP_PartAandB_redactedsignature 

Redacted CSR Synopsis 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Hrebien S, Citi V, Garcia-Murillas I, Cutts R, Fenwick K, Kozarewa I, McEwen R, Ratnayake J, Maudsley R, Carr TH, de Bruin EC, Schiavon G, Oliveira M, Turner N. Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial. Ann Oncol. 2019 Jun 1;30(6):945-952. doi: 10.1093/annonc/mdz085.

Turner NC, Alarcon E, Armstrong AC, Philco M, Lopez Chuken YA, Sablin MP, Tamura K, Gomez Villanueva A, Perez-Fidalgo JA, Cheung SYA, Corcoran C, Cullberg M, Davies BR, de Bruin EC, Foxley A, Lindemann JPO, Maudsley R, Moschetta M, Outhwaite E, Pass M, Rugman P, Schiavon G, Oliveira M. BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population. Ann Oncol. 2019 May 1;30(5):774-780. doi: 10.1093/annonc/mdz086.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01625286
• Other Study ID Numbers: D3610C00002; 2011-006312-31 ( EudraCT Number )
• First Posted: June 21, 2012
• Results First Posted: April 1, 2019
• Last Update Posted: January 18, 2023
• Last Verified: December 2022

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:

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