Clinical trial NCT01625286: Investigating Safety, Tolerability and Efficacy of AZD5363 When Combined With Paclitaxel in Breast Cancer Patients
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2012-06-21
Enrollment: 148
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: Dose-limiting Toxicity (DLT) Events - Part A
timeFrame: During Part A DLT evaluation period (Cycle 1, up to 28 days)
measure: Progression Free Survival (PFS) - Part B
timeFrame: 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:
measure: Change in Tumour Size at 12 Weeks
timeFrame: RECIST tumour assessments every 12 weeks
measure: Objective Response Rate (ORR) at Week 12
timeFrame: RECIST tumour assessments every 12 weeks
measure: Best Objective Response (BOR)
timeFrame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
measure: Overall Objective Response Rate
timeFrame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
measure: Number of Subjects Without Progression Disease at Week 12 - Part A
timeFrame: up to 12 weeks
measure: Duration of Response (DOR) - Part B
timeFrame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
measure: Durable Response Rate (DRR) - Part B
timeFrame: From date of randomisation, assessed every 12 weeks (median total treatment duration AZD5363 = 325.5 days; Placebo = 245 days).
measure: Overall Survival - Part B
timeFrame: 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).
Other outcomes:
Locations:
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Paris Cedex 5
country: France
facility: Research Site
city: Pierre Benite CEDEX
country: France
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Chiba-shi
country: Japan
facility: Research Site
city: Chuo-ku
country: Japan
facility: Research Site
city: Fukuoka-shi
country: Japan
facility: Research Site
city: Mitaka-shi
country: Japan
facility: Research Site
city: Oita-shi
country: Japan
facility: Research Site
city: Osaka-shi
country: Japan
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Estado de México
country: Mexico
facility: Research Site
city: Juchitan
country: Mexico
facility: Research Site
city: Monterrey
country: Mexico
facility: Research Site
city: Oaxaca
country: Mexico
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Miraflores
country: Peru
facility: Research Site
city: Singapore
country: Singapore
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Malaga
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Plymouth
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Justin Lindemann, MBChB MBA
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.