Fulvestrant, Ipatasertib and CDK4/6 Inhibition in Metastatic ER+/HER2- Breast Cancer Patients Without ctDNA Suppression

NCT04920708 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: CCR5214
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 13

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.

Conditions

Metastatic Breast Cancer; ER+ Breast Cancer; Advanced Breast Cancer

Keywords

Fulvestrant; Palbociclib; Ipatasertib; ctDNA

Outcome Measures

Primary Outcomes (1)

• Assess progression free survival (PFS)

  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.

  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

Secondary Outcomes (5)

• To assess the AEs/SAEs for patients on palbociclib/fulvestrant/ipatasertib compared to palbociclib/fulvestrant alone

  51 months (treatment duration + follow-up duration)

• Assess overall survival

  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

Other Outcomes (6)

• Report progression-free survival by ctDNA genomic alterations

  51 months (treatment duration + follow-up duration)

• Report progression free survival (PFS) in patients with undetectable ctDNA and those with detected ctDNA at C1D1 with and without suppression at C1D15.

  51 months (treatment duration + follow-up duration)

• Report overall survival (OS) by early ctDNA status at C1D1 and C1D15

  51 months (treatment duration + follow-up duration)

Study Arms (4)

Palbociclib + Fulvestrant + Ipatasertib (Interventional arm)

EXPERIMENTAL

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.

Drug: Ipatasertib 300mg; Drug: Fulvestrant 500g; Drug: Palbociclib 75mg-125mg

Palbociclib + Fulvestrant (Comparison arm)

ACTIVE COMPARATOR

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.

Drug: Fulvestrant 500g; Drug: Palbociclib 75mg-125mg

Standard of Care (No ctDNA observational arm)

ACTIVE COMPARATOR

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.

Drug: Fulvestrant 500g; Drug: CDK4/6 Inhibitor

Standard of Care (Low ctDNA observational arm)

ACTIVE COMPARATOR

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.

Drug: Fulvestrant 500g; Drug: CDK4/6 Inhibitor

Interventions

Ipatasertib 300mg DRUG

Ipatasertib 300mg once daily. Oral administration. Treatment is continuous daily for 21 days, followed by 7 days off, to complete a 28 day cycle.

Also known as: RG7440

Palbociclib + Fulvestrant + Ipatasertib (Interventional arm)

Fulvestrant 500g DRUG

Fulvestrant 500mg administered intramuscularly in the buttocks slowly (1-2 minutes per injection) as two 5-mL injections (one in each buttock). Administered days 1 and 15 of Cycle 1. For subsequent cycles, patients will receive fulvestrant as described above in the clinic on Day 1 of each cycle or approximately every 4 weeks.

Also known as: Faslodex

Palbociclib + Fulvestrant (Comparison arm); Palbociclib + Fulvestrant + Ipatasertib (Interventional arm); Standard of Care (Low ctDNA observational arm); Standard of Care (No ctDNA observational arm)

Palbociclib 75mg-125mg DRUG

Palboclicib 75mg-125mg once daily, dependent on toxicities. Oral administration. Treatment is continuous daily for 21 days, followed by 7 days off, to complete a 28 day cycle.

Also known as: Ibrance

Palbociclib + Fulvestrant (Comparison arm); Palbociclib + Fulvestrant + Ipatasertib (Interventional arm)

CDK4/6 Inhibitor DRUG

CDK4/6 inhibitor. As per current standard of care regime for ER+/HER2- breast cancer.

Also known as: Abemaciclib / Ribociclib / Palbociclib

Standard of Care (Low ctDNA observational arm); Standard of Care (No ctDNA observational arm)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 2.
• 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
• Total bilirubin \<= 1.5 times the upper limit of normal (ULN). Patients with known Gilbert syndrome may be enrolled if bilirubin \<= 3 times ULN
• AST and ALT \<= 2.5 times ULN. Patients with documented liver or bone metastases may have AST and ALT \<= 5 times ULN
• ALP \<= 2 times ULN. Patients with known liver involvement may have ALP \<= 5 times ULN. Patients with known bone involvement may have ALP \<= 7 times ULN
• Serum creatinine \<= 1.5 times ULN or creatinine clearance \>= 50 mL/min using the Cockcroft-Gault formula
• INR \< 1.5 times ULN and aPTT \< 1.5 times ULN. Patients requiring anticoagulation should receive low-molecular-weight heparin or a direct oral anticoagulant

You may not qualify if:

• 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
• Symptomatic cardiac failure (NYHA class II to IV or LVEF \< 50%), uncontrolled hypertension, cardiac dysrhythmia requiring medication, significant or symptomatic bradycardia, long QT syndrome, family history of congenital long QT syndrome or idiopathic sudden death
• Cerebrovascular accident or transient ischemic attack within 12 months
• Known risk factors for prolonged QT interval or Torsade de Pointes
• Uncorrected hypomagnesaemia or hypokalaemia of Grade 3 or higher
• Systolic blood pressure \> 160 mmHg or \< 90 mmHg

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Pfizer: collaborator
• Hoffmann-La Roche: collaborator

Study Sites (13)

Addenbrookes Hospital

Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

Location

Royal Cornwall Hospital

Truro, Cornwall, TR1 3LQ, United Kingdom

Location

Mount Vernon Cancer Centre

London, Surrey, HA6 2RN, United Kingdom

Location

Velindre Cancer Centre

Cardiff, Wales, CF14 2TL, United Kingdom

Location

Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

Location

Beatson West of Scotland Cancer Centre

Glasgow, United Kingdom

Location

Royal Free Hospital

London, NW3 2QC, United Kingdom

Location

Royal Marsden NHS Foundation Trust

London, SW3 6JJ, United Kingdom

Location

Imperial College University Hospitals NHS Trust

London, W2 1NY, United Kingdom

Location

University College London Hospital

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M20 4BX, United Kingdom

Location

Nottingham City Hospital

Nottingham, United Kingdom

Location

Oxford University Hospitals

Oxford, OX3 7LE, United Kingdom

Location

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MeSH Terms

Conditions

Breast Neoplasms

Interventions

ipatasertib; Fulvestrant; palbociclib; abemaciclib; ribociclib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Alicia Okines

  Royal Marsden NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients starting standard of care CDK4/6 inhibitors and fulvestrant will have ctDNA assessment at Cycle 1 Day 1 (C1D1) and Cycle 1 Day 15 (C1D15). Patients with high ctDNA levels at C1D1 and D15 will be randomised in a 1:1 ratio to CDK4/6 inhibitor + fulvestrant (comparison arm) or palbociclib + fulvestrant + ipatasertib (interventional arm). Patients with ctDNA suppressed at C1D15 will continue standard of care, fulvestrant+CDK4/6 inhibitor (observational arm). The first 100 patients of this group will be followed for PFS, OS and ctDNA collection. Patients with no detectable ctDNA at screening will continue on standard of care. The first 50 of this group will be followed for PFS, OS, time to next treatment, and time to chemotherapy.

Study Record Dates

• First Submitted: May 27, 2021
• First Posted: June 10, 2021
• Study Start: December 28, 2022
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: April 14, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (13)