Randomised Open-label Phase II Study of Induction Standard of Care Fulvestrant and CDK4/6 Inhibition With the Addition of Ipatasertib in Metastatic ER+/HER2- Breast Cancer Patients Without ctDNA Suppression
Overview
- Phase
- Phase 2
- Intervention
- Fulvestrant 500g
- Conditions
- Metastatic Breast Cancer
- Sponsor
- Royal Marsden NHS Foundation Trust
- Enrollment
- 57
- Locations
- 25
- Primary Endpoint
- Assess progression free survival (PFS)
- Status
- Active, not recruiting
- Last Updated
- 18 days ago
Overview
Brief Summary
Analysis of circulating tumour DNA (ctDNA) found in a patient's peripheral blood can identify cancer progression and predict a patient's response to therapy. By using ctDNA analysis and imaging techniques, the FAIM trial aims to determine whether the addition of the experimental drug ipatasertib to a standard combination of the hormone treatment fulvestrant and the targeted agent palbociclib increases progression free survival (PFS) for patients with hormone-receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer.
Detailed Description
Circulating tumour DNA (ctDNA) can be found in the peripheral blood of patients with cancer. ctDNA analysis provides a readily available, serial source of tumour DNA which can be used to monitor disease and predict a patients response to therapy. Relative changes in ctDNA after 15 days of treatment with palbociclib and fulvestrant has been found to strongly predict progression free survival (PFS) in hormone-receptor positive and human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer patients: patients without ctDNA suppression after 2 weeks of treatment had a significantly shorter PFS compared to those with ctDNA suppression, identifying a group of patients who require additional therapy to prevent early progression. The FAIM trial is a randomised, open-label study which will aim to determine whether the addition of ipatasertib to standard of care CDK4/6 inhibitors + fulvestrant increases PFS in patients who lack ctDNA suppression after 15 days of treatment. Patients starting standard of care CDK4/6 inhibitors + fulvestrant will have a ctDNA assessment on cycle 1 day 1 (C1D1) and cycle 1 day 15 (C1D15). Those with high ctDNA levels at C1D15 will be randomised on a 1:1 basis to either standard of care (CDK4/6 inhibitors + fulvestrant) or standard of care plus the experimental drug ipatasertib (CDK4/6 inhibitor + fulvestrant + ipatasertib). Patients with ctDNA suppression at C1D15 will continue standard of care (fulvestrant+CDK4/6 inhibitor); the first 100 patients of this group will be followed for PFS and ctDNA collection. Patients without detectable ctDNA on C1D1 will be followed and treated according standard of care; the first 50 patients of this group will be followed for PFS, overall survival (OS), time to next treatment, and time to chemotherapy. Progression free survival will be monitored using RECIST 1.1.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histological diagnosis of metastatic or inoperable locally advanced ER positive/HER2 negative breast cancer. Assessment of ER and HER2 status as per local assessment. Histologically proven primary ER+ (Allred score 3/8 or greater, or stain in more than 1% of cancer cells) and HER2- (immunohistochemistry 0/1+ or negative by in situ hybridization) breast cancer as determined by local laboratory.
- •Willingness to consent for an archival tumour tissue sample (of advanced disease) to be requested for transfer to the Royal Marsden during study screening for future analysis. Patients without a metastatic biopsy are eligible if archival tumour from the breast primary tumour is available, but only after discussion with the Chief Investigator (see section 7.3.1). (PI assessment that a biopsy is not clinically appropriate will be required as evidence before discussion with the CI).
- •Previously treated with no more than one prior line of chemotherapy for advanced disease.
- •Patients eligible according to standard of care for fulvestrant in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib).
- •Patients must have progressed on or within 1 month from stopping prior endocrine therapy for advanced disease, or relapsed on or within 12 months of completing adjuvant endocrine therapy.
- •Measurable disease according to RECIST 1.1 or assessable bone disease (lytic or mixed lytic/sclerotic).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
- •Adequate bone marrow, renal, and liver function within 14 days prior to the first study treatment on Day 1 of Cycle 1, defined as:
- •Neutrophils (ANC \>= 2000/uL), haemoglobin \>= 90 g/L, platelet count \>= 100 x 10\^9/L
- •Serum albumin \>= 3 g/dL
Exclusion Criteria
- •Prior exposure to adjuvant CDK4/6 inhibitors (abemaciclib, palbociclib, or ribociclib) for early breast cancer less than 12 months (52 weeks or 365 days) prior to breast cancer recurrence.
- •Prior treatment with fulvestrant for advanced breast cancer.
- •Prior treatment with an AKT inhibitor, PIK3CA inhibitor, or mTOR inhibitor in any setting.
- •History of malabsorption syndrome or other condition that would interfere with enteral absorption, or inability or unwillingness to swallow oral medication.
- •Systemic chemotherapy within 14 days or endocrine therapy within 7 days prior to registration.
- •Major surgery within 4 weeks prior to registration.
- •Palliative radiotherapy within 14 days prior to registration.
- •Known leptomeningeal disease, untreated brain metastases, spinal cord compression, or symptomatic brain metastases requiring steroids.
- •Clinically significant, uncontrolled cardiac disease or cardiac repolarization abnormality, including but not limited to:
- •Angina pectoris, symptomatic pericarditis, coronary artery bypass graft, or myocardial infarction within 12 months prior to study entry
Arms & Interventions
Standard of Care (Low ctDNA observational arm)
Where low ctDNA is detected in screening, patients to be allocated to the observational arm and receive standard of care (Abemaciclib / Ribociclib / Palbociclib + fulvestrant). n = 100.
Intervention: Fulvestrant 500g
Standard of Care (No ctDNA observational arm)
Where no ctDNA is detected in screening, patients to be allocated to the observational arm and receive standard of care (Abemaciclib / Ribociclib / Palbociclib + fulvestrant). n = 50.
Intervention: CDK4/6 Inhibitor
Standard of Care (Low ctDNA observational arm)
Where low ctDNA is detected in screening, patients to be allocated to the observational arm and receive standard of care (Abemaciclib / Ribociclib / Palbociclib + fulvestrant). n = 100.
Intervention: CDK4/6 Inhibitor
Palbociclib + Fulvestrant + Ipatasertib (Interventional arm)
Where high ctDNA is detected in screening, patients to be randomised on a 1:1 basis to interventional arm or comparison arm. Patients randomised to interventional arm receive Palbociclib + Fulvestrant + Ipatasertib. n = 87.
Intervention: Palbociclib 75mg-125mg
Palbociclib + Fulvestrant (Comparison arm)
Where high ctDNA is detected in screening, patients to be randomised on a 1:1 basis to interventional arm or comparison arm. Patients randomised to Comparison arm receive Palbociclib + Fulvestrant. n = 87.
Intervention: Palbociclib 75mg-125mg
Palbociclib + Fulvestrant + Ipatasertib (Interventional arm)
Where high ctDNA is detected in screening, patients to be randomised on a 1:1 basis to interventional arm or comparison arm. Patients randomised to interventional arm receive Palbociclib + Fulvestrant + Ipatasertib. n = 87.
Intervention: Ipatasertib 300mg
Palbociclib + Fulvestrant + Ipatasertib (Interventional arm)
Where high ctDNA is detected in screening, patients to be randomised on a 1:1 basis to interventional arm or comparison arm. Patients randomised to interventional arm receive Palbociclib + Fulvestrant + Ipatasertib. n = 87.
Intervention: Fulvestrant 500g
Palbociclib + Fulvestrant (Comparison arm)
Where high ctDNA is detected in screening, patients to be randomised on a 1:1 basis to interventional arm or comparison arm. Patients randomised to Comparison arm receive Palbociclib + Fulvestrant. n = 87.
Intervention: Fulvestrant 500g
Standard of Care (No ctDNA observational arm)
Where no ctDNA is detected in screening, patients to be allocated to the observational arm and receive standard of care (Abemaciclib / Ribociclib / Palbociclib + fulvestrant). n = 50.
Intervention: Fulvestrant 500g
Outcomes
Primary Outcomes
Assess progression free survival (PFS)
Time Frame: Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 38 months
To compare PFS in patients randomised between palbociclib/fulvestrant/ipatasertib versus standard of care palbociclib-fulvestrant alone, in advanced ER+/HER2- breast cancer patients with trackable mutations and high ctDNA after 2 weeks of CDK4/6 inhibitor/fulvestrant.
Assess progression free survival (PFS)
Time Frame: Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 51 months
To compare PFS in patients randomised between SOC palbociclib/fulvestrant + ipatasertib and SOC CDK4/6 inhibitor/fulvestrant alone, in advanced ER+/HER2- breast cancer patients with trackable mutations and high ctDNA after 2 weeks of CDK4/6 inhibitor/fulvestrant.
Secondary Outcomes
- Use NCI CTCAE V5.0 to assess safety and tolerability of palbociclib/fulvestrant/ipatasertib compared to palbociclib/fulvestrant alone(36 months (treatment duration + follow-up duration))
- Assess overall survival(36 months (treatment duration + follow-up duration))
- Assess objective response rate(36 months (treatment duration + follow-up duration))
- Report progression free survival (PFS) in patients with low ctDNA and high ctDNA(Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 38 months)
- Compare progression free survival (PFS) in the subgroup of advanced ER+/HER2- breast cancer patients(Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 38 months)
- Assess overall survival(51 months (treatment duration + follow-up duration))
- To assess the AEs/SAEs for patients on palbociclib/fulvestrant/ipatasertib compared to palbociclib/fulvestrant alone(51 months (treatment duration + follow-up duration))
- Assess objective response rate(51 months (treatment duration + follow-up duration))
- Report progression free survival (PFS) in patients with low ctDNA and high ctDNA(Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 51 months)
- Compare progression free survival (PFS) in the subgroup of advanced ER+/HER2- breast cancer patients(Time from date of randomisation until the date of first documented progression or date of death from any cause, whichever comes first, assessed up to 51 months)