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

NCT01625286 | Completed Phase 1 Results DMC

• 2 other identifiers: D3610C000022011-006312-31
• Study Type: interventional
• Target: 148
• Locations: 11 countries
• Sites: 41

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.

Conditions

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

Keywords

advanced breast cancer,; metastatic breast cancer,; ER+ve breast cancer,; Estrogen receptor positive breast cancer,; PIK3CA mutated advanced or metastatic breast cancer; AKT inhibitor

Outcome Measures

Primary Outcomes (2)

• Dose-limiting Toxicity (DLT) Events - Part A

  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

  During Part A DLT evaluation period (Cycle 1, up to 28 days)

• Progression Free Survival (PFS) - Part B

  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.

  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)

Secondary Outcomes (8)

• Change in Tumour Size at 12 Weeks

  RECIST tumour assessments every 12 weeks

• Objective Response Rate (ORR) at Week 12

  RECIST tumour assessments every 12 weeks

• Best Objective Response (BOR)

  From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).

• Overall Objective Response Rate

  From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).

• Number of Subjects Without Progression Disease at Week 12 - Part A

  up to 12 weeks

Study Arms (4)

Part A: Intermittent schedule (2/5)

EXPERIMENTAL

See intervention description below.

Drug: AZD5363 when combined with weekly paclitaxel.

Part A: Intermittent schedule (4/3)

EXPERIMENTAL

See intervention description below.

Drug: AZD5363 when combined with weekly paclitaxel.

Part B: AZD5363 combined with paclitaxel

ACTIVE COMPARATOR

See intervention description below.

Drug: AZD5363when combined with weekly paclitaxel.

Part B: paclitaxel combined with placebo

PLACEBO COMPARATOR

See intervention description below.

Drug: A placebo in combination with weekly paclitaxel.

Interventions

AZD5363 when combined with weekly paclitaxel. DRUG

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.

Part A: Intermittent schedule (2/5)

AZD5363when combined with weekly paclitaxel. DRUG

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.

Part B: AZD5363 combined with paclitaxel

A placebo in combination with weekly paclitaxel. DRUG

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.

Part B: paclitaxel combined with placebo

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (41)

Research Site

Plovdiv, 4004, Bulgaria

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Sofia, 1330, Bulgaria

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Calgary, Alberta, T2N 4N2, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Montreal, Quebec, H4A 3T2, Canada

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Québec, Quebec, G1S 4L8, Canada

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Brno, 656 53, Czechia

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Paris, 75248, France

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Pierre-Bénite, 69310, France

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Villejuif, 94805, France

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Chiba, 260-8717, Japan

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Chūōku, 104-0045, Japan

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Fukuoka, 811-1395, Japan

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Mitaka-shi, 181-8611, Japan

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Osaka, 540-0006, Japan

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Ōita, 870-0854, Japan

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Estado de México, 50080, Mexico

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Juchitán, 7000, Mexico

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Monterrey, 64460, Mexico

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Oaxaca City, 68000, Mexico

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Lima, 15036, Peru

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Lima, L 41, Peru

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Lima, LIMA 27, Peru

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Miraflores, 15046, Peru

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Singapore, 119228, Singapore

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Seongnam-si, 13620, South Korea

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Seoul, 03080, South Korea

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Seoul, 03722, South Korea

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Seoul, 135-710, South Korea

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Barcelona, 08025, Spain

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Madrid, 08035, Spain

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Madrid, 28040, Spain

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Madrid, 28041, Spain

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Málaga, 29010, Spain

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Valencia, 46010, Spain

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Glasgow, G12 0YN, United Kingdom

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Leicester, LE1 5WW, United Kingdom

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London, SW3 6JJ, United Kingdom

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Manchester, M20 4BX, United Kingdom

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Plymouth, PL6 8DH., United Kingdom

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Sutton, SM2 5PT, United Kingdom

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Related Publications (2)

• 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.

  PMID: 30860573 DERIVED

• 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.

  PMID: 30860570 DERIVED

Related Links

• CSPandAmendments\_redacted
• SAP\_PartAandB\_redactedsignature
• SAP\_PartAandB\_redactedsignature
• Redacted CSR Synopsis

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

QoL, PK/PD \& efficacy response modelling were considered non-key secondary endpoints and not disclosed at this time. QoL data was limited and considered exploratory, PK/PD and modelling were not reported in CSR. Diarrhoea burden is reported with AEs

Results Point of Contact

• Title: AstraZeneca Clinical
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Justin Lindemann, MBChB MBA

  AstraZeneca

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 10, 2012
• First Posted: June 21, 2012
• Study Start: October 3, 2012
• Primary Completion: January 28, 2017
• Study Completion: October 3, 2022
• Last Updated: January 18, 2023
• Results First Posted: April 1, 2019

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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

Locations

CZ (1); ME (4); SG (1); ES (6); PE (4); JP (6); CA (4); BU (2); KR (4); FR (3); GB (6)