AZD4547 & Anastrozole or Letrozole (NSAIs) in ER+ Breast Cancer Patients Who Have Progressed on NSAIs (RADICAL)

NCT01791985 | Completed Phase 1 Results DMC

• 2 other identifiers: C/23/20112011-000454-32
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 7

Brief Summary

This study is looking at a new drug called AZD4547 which is being tested for the treatment of oestrogen receptor positive breast cancer. AZD4547 is a drug which specifically "blocks" proteins called fibroblast growth factor receptors (FGFR1) that are involved in the processes that help cancer cells to grow. These proteins may also be responsible for the development of resistance to hormonal therapies used to treat some breast cancers. AZD4547 is not yet approved for use in breast cancer and is therefore being used in this study as a research drug. The investigators will also test the theory that it is not necessary for high levels of FGFR1 to be present in the body to see benefit from AZD4547. (Stage 1 only)

Conditions

Breast Cancer

Keywords

Breast Cancer; AZD4547; Safety Run-In; FGFR1; ER positive breast cancer; Single arm phase IIa study

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Serious Adverse Events (SAEs)

  Safety and tolerability of AZD4547 to be used in combination with a standard dose of anastrozole or letrozole, as assessed by Dose limiting toxicity (DLT) This is the primary outcome measure in the Safety Run-In part of the study.

  Dose limiting toxicity (DLT) assessment window - days 1 to 28 of cycle 1

• Proportion of Tumour Size Change at 12 Weeks (or Progression if Prior to Week 12)

  This is the primary outcome measure in the Randomised Phase IIa part of the study. This is the proportion of tumour size change from baseline to week 12 (or progression if prior to week 12) based on local review of results.

  12 weeks

Secondary Outcomes (4)

• Proportion of Tumour Size Change at 6, 20 and 28 Weeks

  6, 20 and 28 weeks

• Tumour Response (RECIST Criteria) at 6, 12, 20 and 28 Weeks

  6, 12, 20 and 28 weeks

• Objective Response at 6, 12, 20 and 28 Weeks

  6, 12, 20 and 28 weeks

• Progression Free Survival

  42 months

Study Arms (1)

Single arm study

EXPERIMENTAL

NSAI (anastrozole (1mg) or letrozole (2.5mg)), orally, once daily but together with twice daily AZD4547 (80mg). AZD4547 will be given on an intermittent schedule of one week on / one week off.

Drug: AZD4547 / anastrozole or letrozole

Interventions

AZD4547 / anastrozole or letrozole DRUG

Patients will continue or restart the NSAI which they have progressed\* on: either anastrozole (1mg) or letrozole (2.5mg), orally, once daily but together with twice daily AZD4547 (80mg). AZD4547 will be given on an intermittent schedule of one week on / one week off. \*Prior to study entry, patients must have taken anastrozole or letrozole at some stage in their treatment to date for breast cancer; and shown evidence of resistance to this therapy. The NSAI does not have to be the most recent line of treatment.

Single arm study

Eligibility Criteria

• Age: 25 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
• Aged ≥ 25 years of age (N.B. in line with other studies with AZD4574 and due to concerns of possible effects on the immature skeleton)
• Post menopausal women. Women will be considered postmenopausal if they have had a bilateral oophorectomy or the following specific requirements apply:
• Safety run-in:
• Women under 50 years old would be considered post-menopausal if they have been amenorrhoeic for 24 months and have follicle-stimulating hormone (FSH) and oestradiol levels in the post-menopausal range. Patients with prior exposure to depot Luteininzing hormone releasing hormones (LHRH) analogues must be 24 months or more following the last administration
• Women aged 50 years and older would be considered post-menopausal if they have been amenorrhoeic for 12 months and patients with prior exposure to depot LHRH analogues must be 12 months or more following the last administration
• Women rendered amenorrhoeic by adjuvant chemotherapy, who were premenopausal or perimenopausal prior to chemotherapy, must have been amenorrhoeic for at least 24 months
• Phase IIa:
• Women under 50 years old would be considered post-menopausal if they have been amenorrhoeic for 24 months and have follicle-stimulating hormone (FSH) and oestradiol levels in the post-menopausal range.
• Women aged 50 years and older would be considered post-menopausal if they have been amenorrhoeic for 12 months
• Women rendered amenorrhoeic by adjuvant chemotherapy, who were premenopausal or perimenopausal prior to chemotherapy, must have been amenorrhoeic for at least 24 months
• Perimenopausal women rendered amenorrhoeic from exposure to depot LHRH analogues\*
• Patients must have taken LHRH analogues for at least 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
• Histological confirmation of breast cancer with documented positive oestrogen receptor status (ER+) of primary or metastatic tumour tissue according to local laboratory parameters

You may not qualify if:

• Treatment with any of the following:
• Safety run-in: more than 1 regimen of endocrine therapy for advanced breast cancer
• previous exposure to any FGFR inhibitor
• Safety run in: more than 1 prior regimen of chemotherapy for advanced breast cancer.
• potent inhibitors or inducers of CYP3A4 or CYP2D6, or substrates of CYP3A4 within 2 weeks prior to first dose of study treatment (3 weeks for St John's Wort)
• major surgery within 4 weeks prior to first dose of study treatment
• radiotherapy with a wide field of radiation within 4 weeks prior to first dose of study treatment; or radiotherapy with a limited field of radiation for palliation within 2 weeks before the first dose of study treatment
• With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at time of starting study
• Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment
• Any evidence of severe or uncontrolled systemic diseases or active infection
• Any of the following cardiac criteria:
• Resting corrected QT interval (QTc) \>470 ms
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
• Inadequate bone marrow reserve or organ function as defined by any one of the following parameters:

Sponsors & Collaborators

• Imperial College London: lead
• Cancer Research UK: collaborator
• AstraZeneca: collaborator

Study Sites (7)

Queen's Hospital, Burton-on-Trent

Burton-on-Trent, Staffs, DE13 0RB, United Kingdom

Location

Russells Hall Hospital, West C8 Admin Office, 2nd Floor

Dudley, West Midlands, DY1 2HQ, United Kingdom

Location

Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Breast Cancer Research Unit, PO Box 97, Hills Road,

Cambridge, CB2 0QQ, United Kingdom

Location

Greater Glasgow Health Board, Beatson West of Scotland Cancer Centre, 1053 Great Western Road,

Glasgow, G12 0YN, United Kingdom

Location

Imperial College Healthcare NHS Trust, Charing Cross Hospital,1st Floor, Department of Medical Oncology, Fulham Palace Road

London, W6 8RF, United Kingdom

Location

The Christie NHS Foundation Trust, Wilmslow Road, Withington

Manchester, M20 4BX, United Kingdom

Location

The Newcastle upon Tyne Hospitals NHS Foundation Trust, Sir Bobby Robson Cancer Trials Research Centre, Freeman Hospital, High Heaton

Newcastle upon Tyne, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Coombes RC, Badman PD, Lozano-Kuehne JP, Liu X, Macpherson IR, Zubairi I, Baird RD, Rosenfeld N, Garcia-Corbacho J, Cresti N, Plummer R, Armstrong A, Allerton R, Landers D, Nicholas H, McLellan L, Lim A, Mouliere F, Pardo OE, Ferguson V, Seckl MJ. Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer. Nat Commun. 2022 Jun 10;13(1):3246. doi: 10.1038/s41467-022-30666-0.

  PMID: 35688802 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

AZD4547; Anastrozole; Letrozole

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Michael Seckl
• Organization: Imperial College London

m.seckl@imperial.ac.uk

+44 (0)20 3311 1421

Study Officials

• Michael Seckl

  Imperial College Healthcare NHS Trust

  PRINCIPAL INVESTIGATOR

• Nicola Cresti

  Newcastle-upon-Tyne Hospitals NHS Trust

  PRINCIPAL INVESTIGATOR

• Richard Baird

  Cambridge University Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• Iain MacPherson

  NHS Greater Glasgow and Clyde

  PRINCIPAL INVESTIGATOR

• Amitabha Chakrabarti

  Poole Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• Mojca Persic

  Burton Hospitals NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• Anne Armstrong

  The Christie NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• Rozenn Allerton

  The Dudley Group NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2013
• First Posted: February 15, 2013
• Study Start: July 1, 2012
• Primary Completion: November 1, 2016
• Study Completion: December 1, 2018
• Last Updated: August 22, 2022
• Results First Posted: August 22, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (7)