Condition category
Cancer
Date applied
27/04/2012
Date assigned
27/04/2012
Last edited
11/04/2013
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Contact information

Type

Scientific

Primary contact

Mr Philip Badman

ORCID ID

Contact details

Imperial College London
Cancer Clinical Trials Unit
1st Floor
Medical Oncology
Charing Cross Hospital
Fulham Palace Road
London
W6 8RF
United Kingdom
radical@imperial.ac.uk

Additional identifiers

EudraCT number

2011-000454-32

ClinicalTrials.gov number

NCT01791985

Protocol/serial number

11456

Study information

Scientific title

A Randomised phase IIa study (with combination safety run-in) to assess the safety and efficacy of AZD4547 In Combination with either anastrozole or letrozole versus exemestane alone in ER positive breast cancer patients who are progressing on current treatment with Anastrozole or Letrozole

Acronym

RADICAL

Study hypothesis

1. To assess the safety and tolerability and determine the dose of AZD4547 to be used in combination with a standard dose of anastrozole/letrozole for the randomised Phase IIa part of the study
2. To assess efficacy based on the change in tumour size at 12 weeks (or progression if prior to week 12) between treatments AZD4547 in combination with anastrozole/letrozole versus exemestane alone in patients who are progressing on treatment with either anastrozole or letrozole in the adjuvant or first line metastatic setting
3. To assess the pharmacokinetics (PK) of anastrozole/letrozole when given alone compared to in combination with AZD4547
4. To describe the PK of AZD4547 when given in combination with anastrozole/letrozole Randomised phase IIa
5. To assess the efficacy based on the change in tumour size at other time points (6 weeks, 20 weeks etc) between treatments AZD4547 in combination with anastrozole/letrozole versus exemestane alone in patients who are progressing on treatment with either anastrozole or letrozole in the adjuvant or first-line metastatic setting
6. To assess the efficacy based on the tumour response RECIST criteria at all time points between AZD4547 in combination with anastrozole / letrozole versus exemestane alone
7. To assess the efficacy based on the objective response rate (ORR) at all time points between AZD4547 in combination with anastrozole / letrozole versus exemestane alone
8. To assess the efficacy based on progression-free survival (PFS) between AZD4547 in combination with anastrozole / letrozole versus exemestane alone
9. To determine whether FGFR1 amplification is required for any benefit demonstrated based on change in tumour size, RECIST categories, ORR and PFS
10. To assess the safety and tolerability of AZD4547 in combination with anastrozole/letrozole compared with exemestane alone


More details can be found at http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=11456

Please note that as of 11/04/2013, the following changes were made to the trial record:
1. The anticipated start date was updated from 30/04/2012 to 23/07/2012
2. The anticipated end date was updated from 28/02/2015 to 30/04/2015

Ethics approval

First MREC, 23 December 2011 ref: 11/EM/0393

Study design

Randomised Phase II Interventional preceded by a Phase 1b Safety Run-in

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Breast Cancer

Intervention

Current interventions as of 15/08/2012:
Safety Run-in: Initially, patients continue to receive single agent treatment which they have progressed on: either anastrozole (1mg) or letrozole (2.5mg), orally, once daily for 7 days. N.B. this must be preceded by a minimum of 21 days of anastrozole or letrozole treatment prior to study entry. Oral AZD4547 will then be added to this ongoing non-steroidal aromatase inhibitor (either anastrozole or letrozole) therapy twice daily but on an intermittent schedule of one week on/one week off.
Randomised Phase IIa: Patients will be stratified by FGFR1 FISH level and randomised to receive either:
Arm A: anastrozole or letrozole + AZD4547 in combination (experimental arm)
Arm B: exemestane alone (control arm)

Patients in the experimental arm will continue to receive the treatment which they have progressed on: either anastrozole (1mg) or letrozole (2.5mg), orally, once daily but together with twice daily AZD4547. AZD4547 will be given on an intermittent schedule of one week on / one week off. The dose level for AZD4547 will be determined from the safety run-in. Patients must have been on anastrozole or letrozole for a minimum of 28 days prior to study entry.

Patients in the control arm will receive once daily exemestane (25mg).

Previous interventions until 15/08/2012:
Initially, patients continue to receive single agent treatment which they have progressed on: either anastrozole (1mg) or letrozole (2.5mg), orally, once daily for 7 days. N.B. this must be preceded by a minimum of 21 days of anastrozole or letrozole treatment prior to study entry. Oral AZD4547 will then be added to this ongoing non-steroidal aromatase inhibitor (either anastrozole or letrozole) therapy twice daily but on an intermittent schedule of one week on/one week off.

Intervention type

Other

Phase

Phase I/II

Drug names

Primary outcome measures

Current primary outcome measures as of 15/08/2012:
For the Safety Run-in:
Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)
For the Randomised Phase IIa:
Change in tumour size at 12 weeks (or progression if prior to week 12)

Previous primary outcome measures until 15/08/2012:
Change in tumour size at week 12 (or progression if prior to week 12)

Secondary outcome measures

Current secondary outcome measures as of 15/08/2012:
For the Safety Run-in:
1. Pharmacokinetic (PK) parameters of anastrozole or letrozole when given alone and in combination with AZD4547
2. PK parameters of AZD4547 when given in combination with anastrozole or letrozole.
3. Safety and tolerability as assessed by adverse events (AEs)
For the Randomised Phase IIa:
1. Change in tumour size at other time points (6 weeks, 20 weeks etc)
2. Tumour response RECIST criteria with 4 categories: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD)
3. Objective response rate (ORR) with 2 categories: CR or PR, SD or PD
4. Progression-free survival (PFS) is time from randomisation to PD (RECIST)

Previous secondary outcome measures until 15/08/2012:
1. Response rate of tumours:
2. Pharmacokinetic parameters of anastrozole or letrozole
3. Pharmacokinetic (PK) parameters of anastrozole or letrozole when given alone and in combination with AZD4547
4. Progression-free survival (PFS)
5. Safety and tolerability of study drug
6.Tumour response

Overall trial start date

23/07/2012

Overall trial end date

30/04/2015

Reason abandoned

Eligibility

Participant inclusion criteria

Current inclusion criteria as of 10/04/2013:
1. Written (signed and dated) informed consent and be capable of cooperating with treatment and follow-up.
2. Aged 25 years of age or over
3. Post menopausal women
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
5. Histological confirmation of breast cancer with documented positive oestrogen receptor status (ER+) of primary or metastatic tumour tissue according to local laboratory parameters.
6. Randomised phase IIa only: Mandatory provision of tumour biopsy for AstraZeneca central laboratory confirmation of FGFR1 status by FISH.
7. Fulfils criteria for previous treatment of breast cancer:
7.1. Relapse during a single regimen of adjuvant endocrine therapy with either anastrozole or letrozole
OR
7.2. Progression during first line endocrine therapy with a nonsteroidal AI for advanced breast cancer (metastatic disease or locally advanced disease which is not amenable to treatment with curative intent). Coadministration of a targeted agent with the nonsteroidal AI is permitted providing all toxicities have recovered to CTCAE Grade 1 or below. Safety run-in only: 1 prior regimen of chemotherapy in the advanced setting is permitted. Chemotherapy administered in the adjuvant setting is permitted. Randomised phase IIa only: Chemotherapy administered in the adjuvant setting is permitted.
8. Safety run-in only: At least one lesion (measurable and/or nonmeasurable) that can be accurately assessed by CT/MRI/plain xray at baseline and follow up visits. Randomised phase IIa only: At least one lesion greater than or equal to 10mm in the longest diameter at baseline that can be accurately measured with CT/MRI at baseline and is suitable for accurate repeated measurements.
9. Safety run-in: Study entry must be preceded by a minimum of 21 days of anastrozole or letrozole treatment
Randomised phase IIa: Study entry must be preceded by a minimum of 28 days of anastrozole or letrozole treatment

Previous inclusion criteria as of 13/08/2012:
1. Written (signed and dated) informed consent and be capable of cooperating with treatment and follow-up.
2. Aged 25 years of age or over
3. Post menopausal women
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
5. Histological confirmation of breast cancer with documented positive oestrogen receptor status (ER+) of primary or metastatic tumour tissue according to local laboratory parameters.
6. Randomised phase IIa only: Mandatory provision of tumour biopsy for AstraZeneca central laboratory confirmation of FGFR1 status by FISH.
7. Fulfils criteria for previous treatment of breast cancer:
7.1. Relapse during a single regimen of adjuvant endocrine therapy with either anastrozole or letrozole
OR
7.2. Progression during first line endocrine therapy with a nonsteroidal AI for advanced breast cancer (metastatic disease or locally advanced disease which is not amenable to treatment with curative intent). Coadministration of a targeted agent with the nonsteroidal AI is permitted providing all toxicities have recovered to CTCAE Grade 1 or below. Safety run-in only: 1 prior regimen of chemotherapy in the advanced setting is permitted. Chemotherapy administered in the adjuvant setting is permitted. Randomised phase IIa only: Chemotherapy administered in the adjuvant setting is permitted.
8. Safety run-in only: At least one lesion (measurable and/or nonmeasurable) that can be accurately assessed by CT/MRI/plain xray at baseline and follow up visits. Randomised phase IIa only: At least one lesion greater than or equal to 10mm in the longest diameter at baseline that can be accurately measured with CT/MRI at baseline and is suitable for accurate repeated measurements.

Previous inclusion criteria until 13/08/2012
4. Eastern Cooperative Oncology Group (ECOG) performance status 01 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
8. Safety run-in only: At least one lesion (measurable and/or nonmeasurable) that can be accurately assessed by CT/MRI/plain xray at baseline and follow up visits. Randomised phase IIa only: At least one lesion equal to 10mm in the longest diameter at baseline that can be accurately measured with CT/MRI at baseline and is suitable for accurate repeated measurements.

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

UK Sample Size: 99

Participant exclusion criteria

1. Treatment with any of the following:
1.1. More than 1 regimen of endocrine therapy for advanced breast cancer
1.2. Previous exposure to any FGFR inhibitor
1.3. Safety run in only: more than 1 prior regimen of chemotherapy for advanced breast cancer Randomised phase IIa only: any prior chemotherapy for advanced breast cancer;
1.4. 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);
1.5. Major surgery within 4 weeks prior to first dose of study treatment;
1.6. Radiotherapy with a wide field of radiation within 4 weeks prior to first dose of study treatment;
1.7. Radiotherapy with a limited field of radiation for palliation within 2 weeks before the first dose of study treatment.
2. With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at time of starting study.
3. 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.
4. Any evidence of severe or uncontrolled systemic diseases or active infection.
5. Any of the following cardiac criteria:
5.1. Mean resting corrected QT interval (QTc) >470 ms obtained from 3 electrocardiograms (ECGs);
5.2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block;
5.3. 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.
6. Inadequate bone marrow reserve or organ function as defined by: Haemoglobin < 9.0 g/dL; Absolute neutrophil count (ANC) < 1.5 x 109 /L; Platelet count < 100 x 109 /L; Alanine aminotransferase > 2.5 x ULN if no demonstrable liver metastases or > 5 x ULN in the presence of liver metastases; Aspartate aminotransferase > 2.5 x ULN if no demonstrable liver metastases or > 5 x ULN in the presence of liver metastases; Total bilirubin > 1.5 x ULN if no demonstrable liver metastases or > 3 x ULN in the presence of liver metastases; Creatinine > 1.5 times ULN or creatinine clearance <50ml/min; Corrected calcium > ULN; Phosphate > ULN.
7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated IMP or previous significant bowel resection that would preclude absorption of AZD4547 or exemestane or anastrozole or letrozole.
8. History of hypersensitivity to AZD4547 or exemestane or anastrozole or letrozole.
9. History of another malignancy within 5 yrs prior to starting study treatment, except adequately treated basal or squamous cell carcinoma of the skin, carcinoma of the cervix and the disease under study.
10. Any of the following ophthalmological criteria:
10.1. Current evidence or previous history of retinal pigmented epithelium detachment (RPED); 10.2. Previous laser treatment or intraocular injection for treatment of macular degeneration;
10.3. Current evidence or previous history of dry or wet age-related macular degeneration;
10.4. Current evidence or previous history of retinal vein occlusion (RVO);
10.5. Current evidence or previous history of retinal degenerative diseases (e.g.hereditary);
10.6. Current evidence or previous history of any other clinically relevant chorioretinal defect.
11. Concurrent treatment with another investigational agent or use of another investigational agent within 30 days or 5 half lives, whichever is longer, preceding the first dose of study treatment
12. Concurrent treatment with prohibited medications and wash out period for that drug will not have been completed before starting study medication (see Appendix B of protocol)

Recruitment start date

23/07/2012

Recruitment end date

30/04/2015

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Imperial College London
London
W6 8RF
United Kingdom

Sponsor information

Organisation

Imperial College London (UK)

Sponsor details

Joint Research Compliance Office
Room 510C
5th Floor
Lab Block
Charing Cross hospital
Fulham Palace Road
London
W6 8RF
United Kingdom
+44 (0)20 3311 0204
gary.roper@imperial.ac.uk

Sponsor type

University/education

Website

http://www3.imperial.ac.uk/

Funders

Funder type

Charity

Funder name

AstraZeneca (UK)

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United Kingdom

Funder name

Cancer Research UK

Alternative name(s)

CRUK

Funding Body Type

private sector organisation

Funding Body Subtype

other non-profit

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes