| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ER Positive Progressing Breast Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancer with documented positive oestrogen receptor status (ER+) of primary or metastatic tumour tissue. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
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| E.2.2 | Secondary objectives of the trial |
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 |
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| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
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| E.3 | Principal 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. Prior chemotherapy in the advanced and adjuvant setting is permitted.
o Prior treatment with exemestane with or without everolimus is permitted.
*HER2-positive breast cancer patients should have been offered at least one prior line of HER2 directed therapy
**Advanced breast cancer: metastatic disease or locally advanced disease which is not amenable to treatment with curative intent
***anastrozole or letrozole does not have to be the most recent therapy
8. Safety run-in: At least one lesion (measurable and/or non-measurable) that can be accurately assessed by CT/MRI/plain x-ray at baseline and follow up visits
Phase IIa: At least one lesion ≥ 10mm in the longest diameter at baseline (or ≥ 15mm in the short axis for nodal disease) that can be accurately measured with CT/MRI at baseline and is suitable for accurate repeated measurements. Patients with bone only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can be accurately assessed by CT or MRI.
9. Safety run-in: Study entry must be preceded by a minimum of 21 days of anastrozole or letrozole treatment
Phase IIa: No set duration of anastrozole or letrozole treatment prior to study entry.
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| E.4 | Principal 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 < 9.0 g/dL (<90.0 g/L)
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 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 macular degeneration
o Current evidence or previous history of soft drusen, drusenoid RPE detachment and wet macular degeneration
o Current evidence or previous history of retinal vein occlusion (RVO)
o Current evidence or previous history of retinal degenerative diseases (e.g. hereditary)
*Patients with uncontrolled glaucoma or intra-ocular pressure >21 mmHg at screening should be referred for ophthalmological management and the condition controlled prior to first dose of study treatment.
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 treat ment
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)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety run-in
Safety and tolerability of AZD4547 to be used in combination with a standard dose of anastrozole or letrozole, as assessed by Dose-limiting toxicity
Phase IIa
Change in tumour size at 12 weeks (or progression if prior to week 12)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis
An interim analysis will occur after 20 patients are recruited into the study (including patients in the safety run in phase) and have completed their 12-week follow up. Recruitment into the study will continue whilst the analysis is being carried out.
Preliminary Final Analysis
Since the study has follow up of efficacy and safety endpoints beyond 12 weeks, the preliminary final analysis may be conducted as soon as the database can be soft locked for the primary endpoint data accumulated up to 12 weeks after the last subject enters the study.
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| E.5.2 | 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
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|
| E.5.2.1 | 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. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| Collection of the last data point for the last patient. Updated definition of end of trial, further to recent guidance issued by NRES |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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