ER Positive Progressing Breast Cancer MedDRA version: 19.0 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: AZD4547
Product Code: AZD4547
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AZD4547
CAS Number: 1035270-39-
Sponsors
Imperial College London
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients must fulfil all of the following criteria. 1. Written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up 2. 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) 3. Post menopausal women. Women will be considered postmenopausal if they have had a bilateral oophorectomy or the following specific requirements apply: Safety run-in: o 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 LHRH analogues must be 24 months or more following the last administration o 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 o 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: o 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. o Women aged 50 years and older would be considered post-menopausal if they have been amenorrhoeic for 12 months o Women rendered amenorrhoeic by adjuvant chemotherapy, who were premenopausal or perimenopausal prior to chemotherapy, must have been amenorrhoeic for at least 24 months o Perimenopausal women rendered amenorrhoeic from exposure to depot LHRH analogues* *Patients must have taken LHRH analogues for at least 6 months 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. Phase IIa: Mandatory provision of tumour biopsy for assessment of oncology biomarkers 7. Fulfils criteria for previous treatment of breast cancer*: Safety run-in: o Relapse during a single regimen of adjuvant endocrine therapy with either anastrozole or letrozole or o Progression during first line endocrine therapy with a non-steroidal AI for advanced breast cancer**. Co-administration of a targeted agent with the non-steroidal AI is permitted providing all toxicities have recovered to CTCAE Grade 1 or below 1 prior regimen of chemotherapy in the advanced setting is permitted. Chemotherapy administered in the adjuvant setting is permitted Phase IIa: o Progressing or progression at some point during breast cancer treatment on endocrine therapy with a non-steroidal AI.*** Co-administration of a targeted agent with the non-steroidal AI is permitted providing all toxicities have recovered to CTCAE Grade 1 or below.
Exclusion criteria
Exclusion criteria: 1. Treatment with any of the following: a. Safety run-in: more than 1 regimen of endocrine therapy for advanced breast cancer b. previous exposure to any FGFR inhibitor c. Safety run in: more than 1 prior regimen of chemotherapy for advanced breast cancer. d. 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) e. major surgery within 4 weeks prior to first dose of study treatment f. 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 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: a. Resting corrected QT interval (QTc) >470 ms b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block c. 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 any one of the following parameters: Haemoglobin 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 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 anastrozole or letrozole 8. History of hypersensitivity to 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:* o Current evidence or previous history of retinal pigmented epithelium detachment (RPED) o Previous laser treatment or intra-ocular injection for treatment of mac
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Stage 1 (Safety run-in): To assess the safety and tolerability and determine the dose of AZD4547 to be used together with a standard dose of anastrozole or letrozole (a class of drugs called non-steroidal aromatase inhibitors) i.e. a dose which does not cause too many unacceptable side effects. This dose of AZD4547 will then be used in stage 2 (phase IIa study). Stage 2 (Phase IIa study): To assess the effectiveness of AZ4547, based on the change in tumour size at 12 weeks (or progression if prior to week 12), when used in combination with either anastrozole or letrozole in ER positive breast cancer patients who have progressed on treatment with either anastrozole or letrozole in any setting. ; Secondary Objective: Stage 1 (Safety run-in) • To assess what the body does (pharmacokinetics) to anastrozole or letrozole when given alone compared to given together with AZD4547. • To describe what the body does (pharmacokinetics) to AZD4547 when given together with anastrozole or letrozole. Stage 2 (Phase IIa study) • To assess the efficacy of AZD4547 in combination with anastrozole or letrozole as measured by change in tumour size at 6 weeks, 20 weeks, then every 8 weeks, as per study plan. • To assess the efficacy of AZD4547 in combination with anastrozole or letrozole as measured by tumour response (RECIST criteria) at 6 weeks, 12 weeks, then every 8 weeks, as per study plan. • To assess the efficacy of the study treatment as measured by the objective response rate (ORR) at 6 weeks, 12 weeks, then every 8 weeks, as per study plan.To assess the efficacy of the study treatment as measured by progression-free survival (PFS) • To assess the safety and tolerability of AZD4547 in combination with ; Primary end point(s): Safety run-in Safety and tolerability of | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety run-in • PK parameters of anastrozole or letrozole when given alone and in combination with AZD4547 • PK parameters of AZD4547 when given in combination with anastrozole or letrozole • Safety and tolerability as assessed by Adverse Events Phase IIa • To assess the efficacy of AZD4547 in combination with anastrozole or letrozole as measured by change in tumour size at 6 weeks, 20 weeks, then every 8 weeks, as per study plan. • To assess the efficacy of AZD4547 in combination with anastrozole or letrozole as measured by the tumour response (RECIST criteria) at 6 weeks, 12 weeks, then every 8 weeks, as per study plan. • To assess the efficacy of the study treatment as measured by the objective response rate (ORR) at 6 weeks, 12 weeks, then every 8 weeks, as per study plan. • To assess the efficacy of the study treatment as measured by progression-free survival (PFS) • To assess the safety and tolerability of AZD4547 in combination with anastrozole or letrozole ; Timepoint(s) of evaluation of this end point: Analysis of the secondary endpoint of Progression Free Survival (PFS)will take place at 30 months (when each subject has been followed up to progression or for a minimum of 6 months). At this time we anticipate that 95% of subjects will have progressed on study treatment. All other secondary efficacy endpoints will also be analysed at this time. | — |
Countries
United Kingdom
Contacts
Public ContactPhilip Badman
Cancer Research UK Imperial Centre: Clinical Trials Section / Imperial Clinical Trials Unit – Cancer
Outcome results
None listed