A Trial of Early Detection of Molecular Relapse With Circulating Tumour DNA Tracking and Treatment With Palbociclib Plus Fulvestrant Versus Standard Endocrine Therapy in Patients With ER Positive HER2 Negative Breast Cancer
NCT ID: NCT04985266
Last Updated: 2024-12-05
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
RECRUITING
Clinical Phase
PHASE2
Total Enrollment
1100 participants
Study Classification
INTERVENTIONAL
Study Start Date
2022-03-30
Study Completion Date
2030-09-01
Brief Summary
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Detection of molecular relapse with circulating tumour DNA analysis can identify which patients with ER positive breast cancer are relapsing on adjuvant endocrine therapy. This trial will aim to demonstrate that palbociclib and fulvestrant, can defer or prevent relapse in patients with ctDNA detected molecular relapse.
The TRAK-ER trial will have two phases, a ctDNA surveillance phase and a randomised therapy trial in patients with positive ctDNA.
The TRAK-ER trial will establish a ctDNA screening programme for patients with ER positive breast cancer receiving adjuvant endocrine therapy with at least a further three years of standard adjuvant endocrine therapy planned. Patients recruited into the TRAK-ER study will have high-risk clinical features to identify patients at higher risk of future relapse.
ctDNA assays will be used to identify which people are at very high risk of relapse (i.e. those with a positive ctDNA result), and randomise this high risk population between standard endocrine therapy versus palbociclib plus fulvestrant for up to two years.
The TRAK-ER trial will have two phases, a ctDNA surveillance phase and a randomised therapy trial in patients with positive ctDNA.
The TRAK-ER trial will establish a ctDNA screening programme for patients with ER positive breast cancer receiving adjuvant endocrine therapy with at least a further three years of standard adjuvant endocrine therapy planned. Patients recruited into the TRAK-ER study will have high-risk clinical features to identify patients at higher risk of future relapse.
ctDNA assays will be used to identify which people are at very high risk of relapse (i.e. those with a positive ctDNA result), and randomise this high risk population between standard endocrine therapy versus palbociclib plus fulvestrant for up to two years.
Detailed Description
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The TRAK-ER trial is a multi-centre, randomised, open-label trial in patients with early stage oestrogen reception positive (ER+) human epidermal growth receptor-2 negative (HER2-) breast cancer, whom have detectable circulating DNA (ctDNA) but no overt macroscopic disease on imaging. TRAK-ER aims to demonstrate that fulvestrant plus palbociclib improves relapse free survival compared to standard endocrine therapy in this patient group.
Despite current treatment, patients with ER+HER2- breast cancer are considered high-risk of distant recurrence for more than the first two decades after initial diagnosis. ctDNA analysis provides a non-invasive, serial source of tumour material which can monitor tumour dynamics and detect molecular relapse.
TRAK-ER will be split into two phases, the first surveillance phase aims to investigate the use of ctDNA to identify and predict the risk of molecular relapse in early ER+/HER2- breast cancer patients whom are receiving adjuvant endocrine therapy with no overt macroscopic disease on imaging. Using ctDNA assays, patients enrolled on TRAK-ER will receive ctDNA testing on a three-monthly basis for up to three years. In the instance where ctDNA is detected, imaging will determine whether overt disease is present. If a patient had a positive ctDNA detection and no macroscopic disease on the staging scan, the patient will be randomised to one of the treatment groups in the second phase of TRAK-ER, the treatment phase.
The treatment phase of TRAK-ER will be a randomised, open-label study which aims to determine whether fulvestrant plus palbociclib (intervention arm) improves relapse free survival compared to standard endocrine therapy (control arm) in patients carried through from the surveillance phase. Patients on each arm will receive treatment (fulvestrant plus palbociclib or standard endocrine therapy) for up to 24 months. Six monthly imaging will determine the presence of macroscopic disease. If macroscopic disease is observed, the patient will discontinue TRAK-ER treatment and commence standard therapy outside of the TRAK-ER trial.
Despite current treatment, patients with ER+HER2- breast cancer are considered high-risk of distant recurrence for more than the first two decades after initial diagnosis. ctDNA analysis provides a non-invasive, serial source of tumour material which can monitor tumour dynamics and detect molecular relapse.
TRAK-ER will be split into two phases, the first surveillance phase aims to investigate the use of ctDNA to identify and predict the risk of molecular relapse in early ER+/HER2- breast cancer patients whom are receiving adjuvant endocrine therapy with no overt macroscopic disease on imaging. Using ctDNA assays, patients enrolled on TRAK-ER will receive ctDNA testing on a three-monthly basis for up to three years. In the instance where ctDNA is detected, imaging will determine whether overt disease is present. If a patient had a positive ctDNA detection and no macroscopic disease on the staging scan, the patient will be randomised to one of the treatment groups in the second phase of TRAK-ER, the treatment phase.
The treatment phase of TRAK-ER will be a randomised, open-label study which aims to determine whether fulvestrant plus palbociclib (intervention arm) improves relapse free survival compared to standard endocrine therapy (control arm) in patients carried through from the surveillance phase. Patients on each arm will receive treatment (fulvestrant plus palbociclib or standard endocrine therapy) for up to 24 months. Six monthly imaging will determine the presence of macroscopic disease. If macroscopic disease is observed, the patient will discontinue TRAK-ER treatment and commence standard therapy outside of the TRAK-ER trial.
Conditions
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ER+ Breast Cancer
HER2-negative Breast Cancer
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
NONE
Study Groups
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Standard endocrine therapy
Standard endocrine therapy will continue for up to 24 months on trial.
Standard endocrine therapies include tamoxifen, and aromatase inhibitors (letrozole, anastrazole, exemestane).
Group Type
ACTIVE_COMPARATOR
Tamoxifen
Intervention Type
DRUG
As per clinical guidelines
Letrozole
Intervention Type
DRUG
As per clinical guidelines
Exemestane
Intervention Type
DRUG
As per clinical guidelines
Anastrozole
Intervention Type
DRUG
As per clinical guidelines
Palbociclib and fulvestrant
Treatment with palbociclib plus fulvestrant will continue for a maximum of 24 months.
Palbociclib will be given orally once a day on days 1-21 of each 28 day cycle.
Fulvestrant 500 mg will be administered on cycle 1 days 1 and 15, cycle 2 day 1 and then every 28 days thereafter (plus or minus 3 days) as two intramuscular injections of 250mg fulvestrant at each visit.
Group Type
EXPERIMENTAL
Palbociclib 125Mg Tab
Intervention Type
DRUG
Palbociclib Tablets, 125 mg orally once daily, beginning on Cycle 1, on Days 1-21 of each 28-day cycle.
Fulvestrant injection
Intervention Type
DRUG
Fulvestrant Intramuscular injections, 500 mg as two injection of 250mg fulvestrant in 5ml solution at each visit. No fulvestrant dose reductions are permitted. Administered on days 1, 15 (plus or minus 3 days), 29 (plus or minus 3 days), and every 28 (plus or minus 3 days) days thereafter.
Interventions
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Palbociclib 125Mg Tab
Palbociclib Tablets, 125 mg orally once daily, beginning on Cycle 1, on Days 1-21 of each 28-day cycle.
Intervention Type
DRUG
Fulvestrant injection
Fulvestrant Intramuscular injections, 500 mg as two injection of 250mg fulvestrant in 5ml solution at each visit. No fulvestrant dose reductions are permitted. Administered on days 1, 15 (plus or minus 3 days), 29 (plus or minus 3 days), and every 28 (plus or minus 3 days) days thereafter.
Intervention Type
DRUG
Tamoxifen
As per clinical guidelines
Intervention Type
DRUG
Letrozole
As per clinical guidelines
Intervention Type
DRUG
Exemestane
As per clinical guidelines
Intervention Type
DRUG
Anastrozole
As per clinical guidelines
Intervention Type
DRUG
Eligibility Criteria
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Inclusion Criteria
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
Neoadjuvant chemotherapy (chemotherapy prior to surgery)
D. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy
E. Lymph node negative and tumour size \> 3 cm after chemotherapy
Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery) 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)
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.
1. Signed informed consent for treatment
2. ECOG performance status 0, 1 or 2
3. Women of childbearing potential should have a negative serum pregnancy test prior to randomisation. If randomisation occurs more than 72 hours prior to receiving the first dose of treatment the test must be repeated before treatment.
4. Female and male patients of childbearing potential must be willing to use an adequate method of contraception (section 4.6), starting with the first dose of treatment through 4 weeks after the last dose of treatment if randomised to standard endocrine therapy and 2 years after the last dose of fulvestrant if randomised to fulvestrant and palbociclib. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. Female patients will be deemed not of childbearing potential if they are postmenopausal or have had irreversible sterilisation
5. Patient has adequate bone marrow and organ function as defined by the following laboratory values:
1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L
2. Platelets ≥ 100 × 109/L
3. Haemoglobin ≥ 100 g/L
4. INR ≤1.5
5. Creatinine \<1.5 x ULN and creatinine clearance ≥30ml/min
6. Total bilirubin \< ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.
7. Alanine aminotransferase (ALT) \< 2.5 x ULN
8. Aspartate aminotransferase (AST) \< 2.5 × ULN
6. Patients must be post-menopausal OR
Pre- or peri-menopausal patients or men may be enrolled if they have ovarian/gonadal suppression with licensed GnRH analogues. Patients must have commenced licensed GnRH analogues at least 2 weeks prior to Cycle 1 Day 1 and continue throughout the study if randomised to fulvestrant and palbociclib.
Post-menopausal female patients, as defined by at least one of the following:
* Age ≥60 years;
* Age \<60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and serum estradiol and FSH levels within the institutional laboratory's reference range for post-menopausal females;
* Documented bilateral oophorectomy;
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
Neoadjuvant chemotherapy (chemotherapy prior to surgery)
D. At least one lymph node positive (micrometastasis or macrometastasis) after chemotherapy
E. Lymph node negative and tumour size \> 3 cm after chemotherapy
Neoadjuvant endocrine therapy (endocrine based therapy prior to surgery) 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)
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.
1. Signed informed consent for treatment
2. ECOG performance status 0, 1 or 2
3. Women of childbearing potential should have a negative serum pregnancy test prior to randomisation. If randomisation occurs more than 72 hours prior to receiving the first dose of treatment the test must be repeated before treatment.
4. Female and male patients of childbearing potential must be willing to use an adequate method of contraception (section 4.6), starting with the first dose of treatment through 4 weeks after the last dose of treatment if randomised to standard endocrine therapy and 2 years after the last dose of fulvestrant if randomised to fulvestrant and palbociclib. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient. Female patients will be deemed not of childbearing potential if they are postmenopausal or have had irreversible sterilisation
5. Patient has adequate bone marrow and organ function as defined by the following laboratory values:
1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L
2. Platelets ≥ 100 × 109/L
3. Haemoglobin ≥ 100 g/L
4. INR ≤1.5
5. Creatinine \<1.5 x ULN and creatinine clearance ≥30ml/min
6. Total bilirubin \< ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN.
7. Alanine aminotransferase (ALT) \< 2.5 x ULN
8. Aspartate aminotransferase (AST) \< 2.5 × ULN
6. Patients must be post-menopausal OR
Pre- or peri-menopausal patients or men may be enrolled if they have ovarian/gonadal suppression with licensed GnRH analogues. Patients must have commenced licensed GnRH analogues at least 2 weeks prior to Cycle 1 Day 1 and continue throughout the study if randomised to fulvestrant and palbociclib.
Post-menopausal female patients, as defined by at least one of the following:
* Age ≥60 years;
* Age \<60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and serum estradiol and FSH levels within the institutional laboratory's reference range for post-menopausal females;
* Documented bilateral oophorectomy;
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 therapeutic dose of fulvestrant is not permitted. One subtherapeutic dose of fulvestrant is 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:
1. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
4. 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.
17. Patient with bilateral tumours, or unilateral multifocal cancers with multiple separate primary cancers.(Multifocal cancer that reflects a single primary cancer, in the opinion of the investigator, are eligible)
1. Evidence of recurrent disease (metastatic or local, see section 6.6 for management of patients with potentially curable local recurrences) on staging scans conducted since positive ctDNA result
2. Known hypersensitivity to the excipients of palbociclib plus fulvestrant
3. Any anti-cancer treatment since enrolling in the TRAK-ER study other than hormonal therapy or a bisphosphonate. Prior exposure to fulvestrant is not permitted.
4. Diagnosis of an alternative cancer since enrolment in the trial other than non-melanoma cancer of the skin or cervical carcinoma in situ
5. Patient has had major surgery within 4 weeks prior to starting trial treatment or has not recovered from major side effects of such procedure
6. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with unfractionated heparin, low molecular weight heparin (LMWH), or a direct-acting oral anticoagulant (DOAC such as rivaroxaban or fondaparinux) is allowed
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:
1. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
4. Cardiac arrhythmia.
11. Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1:
* Medications that are strong inducers or inhibitors of CYP3A4 (section 8.5.2)
* Herbal preparations/medications, dietary supplements, fruits (e.g grapefruit, pomelos, starfruit, Seville oranges) and their juice
12. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
13. Known history of HIV (testing not required as part of study screening)
14. Known active Hepatitis B or Hepatitis C (testing not required as part of study screening)
15. Patient has a history of non-compliance to medical regimen
16. 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.
17. Females who are known to be pregnant or breastfeeding.
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 therapeutic dose of fulvestrant is not permitted. One subtherapeutic dose of fulvestrant is 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:
1. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
4. 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.
17. Patient with bilateral tumours, or unilateral multifocal cancers with multiple separate primary cancers.(Multifocal cancer that reflects a single primary cancer, in the opinion of the investigator, are eligible)
1. Evidence of recurrent disease (metastatic or local, see section 6.6 for management of patients with potentially curable local recurrences) on staging scans conducted since positive ctDNA result
2. Known hypersensitivity to the excipients of palbociclib plus fulvestrant
3. Any anti-cancer treatment since enrolling in the TRAK-ER study other than hormonal therapy or a bisphosphonate. Prior exposure to fulvestrant is not permitted.
4. Diagnosis of an alternative cancer since enrolment in the trial other than non-melanoma cancer of the skin or cervical carcinoma in situ
5. Patient has had major surgery within 4 weeks prior to starting trial treatment or has not recovered from major side effects of such procedure
6. Patient is currently receiving warfarin or other coumarin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with unfractionated heparin, low molecular weight heparin (LMWH), or a direct-acting oral anticoagulant (DOAC such as rivaroxaban or fondaparinux) is allowed
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:
1. History of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to trial entry
2. Symptomatic congestive heart failure
3. Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome.
4. Cardiac arrhythmia.
11. Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to Cycle 1 Day 1:
* Medications that are strong inducers or inhibitors of CYP3A4 (section 8.5.2)
* Herbal preparations/medications, dietary supplements, fruits (e.g grapefruit, pomelos, starfruit, Seville oranges) and their juice
12. History of pneumonitis, interstitial lung disease or pulmonary fibrosis
13. Known history of HIV (testing not required as part of study screening)
14. Known active Hepatitis B or Hepatitis C (testing not required as part of study screening)
15. Patient has a history of non-compliance to medical regimen
16. 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.
17. Females who are known to be pregnant or breastfeeding.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Pfizer
INDUSTRY
Sponsor Role
collaborator
AstraZeneca
INDUSTRY
Sponsor Role
collaborator
Institute of Cancer Research, United Kingdom
OTHER
Sponsor Role
collaborator
UNICANCER
OTHER
Sponsor Role
collaborator
Gustave Roussy, Cancer Campus, Grand Paris
OTHER
Sponsor Role
collaborator
Invitae Corporation
INDUSTRY
Sponsor Role
collaborator
Royal Marsden NHS Foundation Trust
OTHER
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Nicholas Turner
Role: PRINCIPAL_INVESTIGATOR
Royal Marsden NHS Foundation Trust
Locations
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Institut de Cancérologie de l'Ouest
Angers, , France
Site Status
RECRUITING
Centre Hospitalier Annecy Genevois_Site d'Annecy
Annecy, , France
Site Status
RECRUITING
Institut du Cancer Avignon Sainte Catherine
Avignon, , France
Site Status
RECRUITING
Centre Hospitalier Simone Veil de Blois
Blois, , France
Site Status
RECRUITING
Institut Bergonié
Bordeaux, , France
Site Status
RECRUITING
Centre Jean Perrin
Clermont-Ferrand, , France
Site Status
RECRUITING
Centre George François Leclerc
Dijon, , France
Site Status
RECRUITING
Groupe Hospitalier Mutualiste de Grenoble
Grenoble, , France
Site Status
RECRUITING
Clinique Chénieux
Limoges, , France
Site Status
RECRUITING
Centre Hospitalier Universitaire de Limoges
Limoges, , France
Site Status
RECRUITING
Centre Léon Bérard
Lyon, , France
Site Status
RECRUITING
Institut Paoli Calmettes
Marseille, , France
Site Status
RECRUITING
Institut de Cancérologie de l'Ouest
Nantes, , France
Site Status
RECRUITING
Centre Antoine Lacassagne
Nice, , France
Site Status
RECRUITING
Gustave Roussy Cancer Campus
Paris, , France
Site Status
RECRUITING
Hôpital Américain de Paris
Paris, , France
Site Status
WITHDRAWN
Institut Godinot
Reims, , France
Site Status
RECRUITING
Centre Eugène Marquis
Rennes, , France
Site Status
RECRUITING
Centre Henri Becquerel
Rouen, , France
Site Status
RECRUITING
CHU de Saint Etienne-Institut de Cancérologie
Saint-Priest-en-Jarez, , France
Site Status
RECRUITING
Institut Claudius Regaud
Toulouse, , France
Site Status
RECRUITING
Barnet Hospital
London, Barnet, United Kingdom
Site Status
NOT_YET_RECRUITING
Royal Cornwall Hospitals NHS Trust
Truro, Cornwall, United Kingdom
Site Status
RECRUITING
University Hospitals Dorset: Royal Bournemouth Hospital
Bournemouth, , United Kingdom
Site Status
RECRUITING
Royal Sussex Hospital
Brighton, , United Kingdom
Site Status
NOT_YET_RECRUITING
Bristol Haematology and Oncology Centre
Bristol, , United Kingdom
Site Status
RECRUITING
Velindre Cancer Centre
Cardiff, , United Kingdom
Site Status
RECRUITING
Velindre University NHS Trust
Cardiff, , United Kingdom
Site Status
RECRUITING
Darlington Memorial Hospital
Darlington, , United Kingdom
Site Status
NOT_YET_RECRUITING
Western General
Edinburgh, , United Kingdom
Site Status
RECRUITING
Royal Devon and Exeter Hospital
Exeter, , United Kingdom
Site Status
RECRUITING
Beatson West of Scotland Cancer Centre
Glasgow, , United Kingdom
Site Status
NOT_YET_RECRUITING
North West Anglia NHS Foundation Trust: Hinchingbrooke Hospital
Huntingdon, , United Kingdom
Site Status
RECRUITING
St James's University Hospital
Leeds, , United Kingdom
Site Status
NOT_YET_RECRUITING
The Clatterbridge Cancer Centre NHS Foundation Trust
Liverpool, , United Kingdom
Site Status
RECRUITING
Barts Health NHS Trust
London, , United Kingdom
Site Status
RECRUITING
Mount Vernon Hospital
London, , United Kingdom
Site Status
RECRUITING
University College London Hospital
London, , United Kingdom
Site Status
RECRUITING
The Royal Free Hospital
London, , United Kingdom
Site Status
RECRUITING
The Royal Marsden NHS Foundation Trust
London, , United Kingdom
Site Status
RECRUITING
Maidstone Hospital
Maidstone, , United Kingdom
Site Status
NOT_YET_RECRUITING
The Christie NHS Foundation Trust
Manchester, , United Kingdom
Site Status
RECRUITING
Nottingham University Hopsitals NHS Trust
Nottingham, , United Kingdom
Site Status
RECRUITING
Oxford Cancer & Haematology Centre, Churchill Hospital,
Oxford, , United Kingdom
Site Status
RECRUITING
North West Anglia NHS Foundation Trust: Peterborough Hospital
Peterborough, , United Kingdom
Site Status
RECRUITING
Derriford Hospital - UHPNT
Plymouth, , United Kingdom
Site Status
RECRUITING
University Hospitals Dorset: Poole Hospital
Poole, , United Kingdom
Site Status
RECRUITING
Weston Park Hospital
Sheffield, , United Kingdom
Site Status
RECRUITING
Somerset NHS Foundation Trust
Taunton, , United Kingdom
Site Status
RECRUITING
Countries
Review the countries where the study has at least one active or historical site.
France
United Kingdom
Central Contacts
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Facility Contacts
Find local site contact details for specific facilities participating in the trial.
Anne Patsouris
Role: primary
PI, Dr Marie Vallee
Role: primary
Dr Julien Grenier
Role: primary
Oliver Arsene
Role: primary
Monica Arnedos
Role: primary
PI: Dr Xavier Durando
Role: primary
Sylvain Ladoire
Role: primary
Elise Bonnet
Role: primary
Dominque Genet
Role: primary
Elise Deluche
Role: primary
Dr Thomas Bachelot
Role: primary
Dr Renaud Sabatier
Role: primary
PI: Dr Marie Robert
Role: primary
PI: Dr Caroline Bailleux
Role: primary
Fabrice Andre
Role: primary
Dr Christelle Jouannaud
Role: primary
Dr Fanny Le Du
Role: primary
Marianne Leheurteur
Role: primary
Gilles Freyer
Role: primary
Dr Florence Dolenc
Role: primary
PI: Neha Dr Chopra
Role: primary
PI: Alistair Thomson
Role: primary
PI: Dr Amit Chakrabarti
Role: primary
PI: Prof Gianfilippo Bertelli
Role: primary
PI: Jeremy Braybrooke
Role: primary
PI: Dr Simon Waters
Role: primary
PI: Dr Simon Waters
Role: primary
TBC
Role: primary
PI: Dr Olga Oikonomidou
Role: primary
PI: Dr Peter Stephens
Role: primary
PI: Prof Iain Macpherson
Role: primary
PI: Dr Indrani Bhattacharya
Role: primary
PI: Dr David Jackson
Role: primary
PI: Professor Carlo Palmieri
Role: primary
PI: Dr Peter Hall
Role: primary
PI: Dr Andreas Makris
Role: primary
PI: Dr Rebecca Roylance
Role: primary
PI: Dr Amna Sheri
Role: primary
Project Manager
Role: primary
PI: Dr Catherine Harper-Wynne
Role: primary
PI: Dr Ciara O'Brien
Role: primary
Sarah Khan, PI
Role: primary
PI: Dr Mark Tuthill
Role: primary
PI: Sarah Ayers
Role: primary
PI: Dr Sidharth Dubey
Role: primary
PI: Dr Amit Chakrabarti
Role: primary
Matthew Winter
Role: primary
PI: Dr Saiqa Spensley
Role: primary
References
Explore related publications, articles, or registry entries linked to this study.
Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013 Mar 28;368(13):1199-209. doi: 10.1056/NEJMoa1213261. Epub 2013 Mar 13.
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BACKGROUND
O'Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K, Andre F, Loibl S, Loi S, Garcia-Murillas I, Cristofanilli M, Huang Bartlett C, Turner NC. The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial. Cancer Discov. 2018 Nov;8(11):1390-1403. doi: 10.1158/2159-8290.CD-18-0264. Epub 2018 Sep 11.
Reference Type
BACKGROUND
Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Gronroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts HJWL, Hackshaw A, Shaw JA, Zimmermann BG; TRACERx consortium; PEACE consortium; Swanton C. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature. 2017 Apr 26;545(7655):446-451. doi: 10.1038/nature22364.
Reference Type
BACKGROUND
Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih lM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 Feb 19;6(224):224ra24. doi: 10.1126/scitranslmed.3007094.
Reference Type
BACKGROUND
Garcia-Murillas I, Chopra N, Comino-Mendez I, Beaney M, Tovey H, Cutts RJ, Swift C, Kriplani D, Afentakis M, Hrebien S, Walsh-Crestani G, Barry P, Johnston SRD, Ring A, Bliss J, Russell S, Evans A, Skene A, Wheatley D, Dowsett M, Smith IE, Turner NC. Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer. JAMA Oncol. 2019 Oct 1;5(10):1473-1478. doi: 10.1001/jamaoncol.2019.1838.
Reference Type
BACKGROUND
Garcia-Murillas I, Schiavon G, Weigelt B, Ng C, Hrebien S, Cutts RJ, Cheang M, Osin P, Nerurkar A, Kozarewa I, Garrido JA, Dowsett M, Reis-Filho JS, Smith IE, Turner NC. Mutation tracking in circulating tumor DNA predicts relapse in early breast cancer. Sci Transl Med. 2015 Aug 26;7(302):302ra133. doi: 10.1126/scitranslmed.aab0021.
Reference Type
BACKGROUND
Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1.
Reference Type
BACKGROUND
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
Reference Type
BACKGROUND
Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Andre F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. doi: 10.1056/NEJMoa1810527. Epub 2018 Oct 20.
Reference Type
BACKGROUND
Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015 Feb;14(2):130-46. doi: 10.1038/nrd4504.
Reference Type
BACKGROUND
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Garnett S, Lindemann JP, Sapunar F, Martin M. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010 Oct 20;28(30):4594-600. doi: 10.1200/JCO.2010.28.8415. Epub 2010 Sep 20.
Reference Type
BACKGROUND
Di Leo A, Jerusalem G, Petruzelka L, Torres R, Bondarenko IN, Khasanov R, Verhoeven D, Pedrini JL, Smirnova I, Lichinitser MR, Pendergrass K, Malorni L, Garnett S, Rukazenkov Y, Martin M. Final overall survival: fulvestrant 500 mg vs 250 mg in the randomized CONFIRM trial. J Natl Cancer Inst. 2014 Jan;106(1):djt337. doi: 10.1093/jnci/djt337. Epub 2013 Dec 7.
Reference Type
BACKGROUND
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
CCR5316
Identifier Type: -
Identifier Source: org_study_id