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

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
• •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.