| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| 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 |
Surveillance Phase:
- To assess the incidence of ctDNA detection in patients with ER positive HER2 negative breast cancer
Treatment Phase:
- To assess whether palbociclib plus fulvestrant improves relapse free survival compared to standard endocrine therapy in patients with ER positive HER2 negative breast cancer with detectable circulating tumour DNA during adjuvant endocrine therapy
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| E.2.2 | Secondary objectives of the trial |
- To assess whether palbociclib plus fulvestrant improves relapse free interval, invasive disease free survival, distant recurrence free survival and overall survival compared with standard endocrine therapy in patients with ER positive HER2 negative breast cancer with detectable circulating tumour DNA during adjuvant endocrine therapy
- To compare relapse free survival in patients who remain ctDNA negative with that of patients ctDNA positive randomised to standard endocrine therapy.
- To assess whether ctDNA clearance on palbociclib plus fulvestrant is associated with improved relapse free survival and overall survival.
- To assess whether ctDNA clearance on standard endocrine therapy is associated with improved relapse free survival and overall survival
- To assess whether palbociclib plus fulvestrant increases ctDNA clearance compared with standard endocrine therapy.
- To assess the tolerability and safety of treatments
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
ELIGIBILTY CRITERIA FOR PATIENT REGISTRATION FOR CTDNA SURVEILLANCE
1. Written informed consent to participate in the trial and to donation of tissue and blood samples
2. Male or female patients aged 18 years or older
3. ECOG performance status 0, 1 or 2 (see https://ecog-acrin.org/resources/ecog-performance-status)
4. Histologically proven primary ER+ (Allred score 6/8 or greater, or stain in ≥10% of cancer cells) and HER2- (immunohistochemistry 0/1+ and/or negative by in situ hybridization) breast cancer as determined by local laboratory
5. Patients with high risk early stage breast cancer according to at least one of the following criteria:
Primary surgery (no other treatment prior to surgery)
A. Four or more involved axillary lymph nodes or positive supraclavicular lymph node at diagnosis, or
B. Tumour size > 5 cm, regardless of lymph node status, or
C. 1-3 involved axillary lymph nodes and at least one of the following; i) Tumour size > 3 cm, ii) histological grade 3 iii) high genomic risk defined as Oncotype Dx Recurrence Score >=26, Prosigna score >=60, EPclin risk score >=4.0, or Mammaprint high risk category, or
D. At least a 15% predicted residual risk of death within 10 years using NHS PREDICT (see appendix A3 on calculating predicted residual risk of death with PREDICT)
Neoadjuvant chemotherapy (chemotherapy prior to surgery)
E. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy
F. Lymph node negative and tumour size > 3 cm after chemotherapy
Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery)
G. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy
H. Lymph node negative and tumour size > 3 cm after chemotherapy
Use the primary surgery criteria - staging tumour size and lymph node status may be either the pathological staging after endocrine therapy or on the initial clinical staging prior to neoadjuvant therapy
6. Available tissue from one archival tumour tissue sample (either from diagnostic biopsy, primary surgery or where available residual disease post-neoadjuvant chemotherapy)
A. Patients with bilateral tumours may enrol if both are ER+ and HER2- and if one archival tissue sample can be provided from each tumour
B. Patients with multifocal breast cancer whose histopathologically examined tumours all meet pathologic criteria for ER+ and HER2- breast cancer, and two archival tissue samples can be provided.
7. No evidence of macroscopic distant metastatic disease or incurable locally advanced disease on staging scans conducted at any time since initial diagnosis.
8. Patients receiving standard endocrine therapy with aromatase inhibitors (letrozole, anastrazole, exemestane), tamoxifen, or combination of such for a minimum of 6 months* and maximum of 7 years duration with an additional three years of endocrine therapy planned. Pre- or peri-menopausal patients may also receive GnRH analogues.
* patients may enrol during the first 6 months of standard endocrine therapy, and wait until at least 6 months of endocrine therapy has been received prior to starting ctDNA surveillance
9. Patients must have had surgery achieving clear margins (as per local guidelines)
10. Female and male patients of reproductive potential must be willing to use an adequate method of contraception for the first three years of the trial, if randomised to standard endocrine therapy for the duration of trial treatment through to at least 4 weeks after the last dose of trial treatment, and if randomised to fulvestrant and palbociclib to 2 years after the last dose of fulvestrant (see section 4.6). Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
11. Patients willing to have frequent blood tests.
ELIGIBILTY CRITERIA FOR ENTRY INTO TREATMENT PHASE
Please refer to the main protocol for inclusion criteria for treatment phase
For all inclusion criteria (France) please refer to the current version of the France Specific Appendix |
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| E.4 | Principal exclusion criteria |
1. Any concurrent or planned treatment for the current diagnosis of breast cancer other than adjuvant endocrine therapy or a bisphosphonate
2. Patients with prior exposure to a CDK 4/6 inhibitor as part of standard of care may enrol only after at least 12 months from completing CDK4/6 therapy.
3. Prior exposure to fulvestrant is not permitted.
4. Prior diagnosis of cancer including prior diagnosis of breast cancer in the previous 5 years, other than for non-melanoma carcinoma of the skin or cervical carcinoma in situ
5. Patients previously entered into a therapeutic trial where experimental therapy is continued post-surgery. Patients who have entered a clinical trial of a CDK4/6 inhibitor in the adjuvant setting are not eligible. Patients who received a CDK4/6 inhibitor only before an operation, with no post-operative adjuvant use, are eligible.
6. Treatment with an unlicensed or investigational product within 4 weeks prior registration to trial
7. Patient has not recovered to ≤ grade 1 (except alopecia or certain other toxicities, which in the opinion of the Investigator should not exclude the patient) from related side effects of any prior antineoplastic therapy, not including side-effects of endocrine therapy
8. Patient with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral medication (e.g. Crohn’s disease, ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection)
9. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’ opinion cause unacceptable safety risks, contraindicate patient participation in the clinical trial or compromise compliance with the protocol.
10. Clinically significant uncontrolled heart disease including any of the following:
a. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry
b. Symptomatic congestive heart failure
c. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
d. Cardiac arrhythmia.
11. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
12. Known history of Human Immunodeficiency Virus (HIV) (testing not required as part of study screening)
13. Known active Hepatitis B or Hepatitis C (testing not required as part of study screening)
14. Females who are known to be pregnant or breastfeeding
15. History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting factor deficiency), other known abnormalities in coagulation or treatment with anticoagulants. Low molecular weight heparin (LMWH), low dose aspirin or clopidogrel are permitted.
16. Child-Pugh class C hepatic impairment or creatinine clearance < 30ml/min.
ELIGIBILTY CRITERIA FOR ENTRY INTO TREATMENT PHASE
Please refer to the main protocol for exclusion criteria for treatment phase.
For all exclusion criteria (France) please refer to the current version of the France Specific Appendix
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Surveillance Phase:
• ctDNA detection – Total ctDNA detection and breakdown by incidence at first ctDNA test verses incidence at subsequent ctDNA tests
Treatment Phase:
• Relapse free survival – Time from randomization to invasive local/regional recurrence (including ipsilateral invasive breast recurrence) or distant recurrence or death from any cause. Patients with second primary invasive cancers (breast or non-breast) would be censored at time of detection.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Surveillance phase:
Duration of ctDNA testing for each participant, may be up to 3 years
Treatment Phase:
Participants will be followed up for 5 years from randomisation. Survival curves will be analysed. |
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| E.5.2 | Secondary end point(s) |
• Relapse free interval – Time from randomisation to invasive local/regional recurrence (including ipsilateral invasive breast recurrence) or distant invasive recurrence. All deaths and second primary invasive cancers (breast or non-breast) would be censored at time of detection.
• Invasive disease free survival – Time from randomisation to invasive local/regional recurrence (including ipsilateral invasive breast recurrence), new breast cancer (ipsilateral or contralateral) or distant recurrence or death from any cause. Patients with non-invasive recurrences or second primary invasive cancers (non-breast) would be censored at time of detection.
• Distant recurrence free survival - Time from randomization to distant invasive breast cancer recurrence or death from any cause. Patients with new contralateral invasive breast cancers or second primary invasive non-breast cancers would be censored at time of detection
• Overall survival – Time from randomisation to death from any cause.
• ctDNA clearance – Absence of detectable ctDNA and disease recurrence at 24 weeks. Additional timepoints will be assessed in exploratory analysis (e.g. 52 weeks).
• Safety and tolerability – Assessed by Adverse Events (AEs) as per CTCAE v5 and quality of life as measured with EQ-5D-5L and EORTC C30 and BR23 questionnaires
• Overt advanced disease (metastatic disease or incurable locally advanced disease) at time of ctDNA detection at the time of first ctDNA detection, and subsequent ctDNA tests.
• Isolated local recurrence (recurrence in ipslilateral breast or ipsilateral regional lymph nodes treatable with potentially curative intent) at the time at time of ctDNA detection at the time of first ctDNA detection, and subsequent ctDNA tests.
• Proportion of recurrences detected by ctDNA – the proportion of recurrences that have ctDNA detected prior to recurrence compared to the total number of recurrences during the period of ctDNA surveillance.
• Level of ctDNA detection – the allele fraction of ctDNA at the time of first ctDNA detection.
• Lead time to recurrence on standard of care – the time from the date of ctDNA detection to invasive local/regional recurrence (including ipsilateral invasive breast recurrence) in the standard of care endocrine therapy group. All deaths and second primary invasive cancers (breast or non-breast) would be censored.
Exploratory endpoints
• Molecular analysis on DNA, RNA or proteins using sequencing of other techniques, on archival tissue, plasma samples, or recurrent disease biopsy.
• Sequential ctDNA analysis in patients randomised to treatment to study temporal changes in ctDNA. Exploratory analysis of ctDNA levels, and mutations, and association with relapse free survival and overall survival.
• Exploratory analysis of ctDNA levels, and mutations, and association with relapse free survival and overall survival.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Data will be collected for evaluation of endpoints for follow-up period of 5 years from registration (surveillance phase) or 5 years from randomisation (treatment phase) for secondary endpoints.
Safety and tolerability of treatment will be assessed from commencement of treatment to follow-up visit 30 days after treatment. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 20 |
| 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 | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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