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.
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.
Inclusion Criteria:
1. 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 >1% of
cancer cells) and HER2- (immunohistochemistry 0/1+ or negative by in situ
hybridization) breast cancer as determined by local laboratory.
2. Be willing to consent for an archival tumour tissue sample (of advanced disease) to be
requested for transfer to the Royal Marsden for future review during study screening.
Patients without a metastatic biopsy may be eligible if archival tumour from the
breast primary tumour is available, but only after discussion with the Chief
Investigator.
3. Previously treated with no more than one prior line of chemotherapy for advanced
disease.
4. Patients eligible according to standard of care for fulvestrant in combination with a
CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib).
5. Patients must have received at least one prior line of hormone therapy for advanced
disease and 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.
6. Measurable disease (RECIST 1.1) or assessable bone disease (lytic or mixed lytic
sclerotic).
7. Eastern Cooperative Oncology Group (ECOG) performance status 0,1 or 2.
8. Estimated life expectancy of at least 3 months.
9. Adequate bone marrow, renal, and liver function within 14 days before the first study
treatment on Day 1 of Cycle 1, defined by the following:
1. Neutrophils (ANC ≥ 1500/μL), Haemoglobin ≥9 g/dL, Platelet count ≥100,000/μL
2. Serum albumin ≥3 g/dL
3. Total bilirubin ≤1.5 x the upper limit of normal (ULN), with the following
exception: patients with known Gilbert syndrome who have serum bilirubin ≤3 x ULN
may be enrolled
4. AST and ALT ≤2.5 x ULN, with the following exception: patients with documented
liver or bone metastases may have AST and ALT ≤5 x ULN.
5. ALP ≤2 x ULN, with the following exceptions: patients with known liver
involvement may have ALP ≤5 x ULN, patients with known bone involvement may have
ALP ≤7 x ULN
6. Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min on the basis of
the Cockcroft-Gault glomerular filtration rate estimation.
7. INR <1.5 x ULN and aPTT <1.5 x ULN. Patients requiring formal anticoagulation
should receive either low-molecular weight heparin or a direct oral
anticoagulant.
10. Fasting glucose ≤150mg/dL and HbA1c ≤7.5%.
11. Negative serum pregnancy test at screening (females of childbearing potential).
12. Patients able to have children must agree to use two highly effective methods of
contraception throughout the study and for 2 years after last dose of fulvestrant and
at least two years after last dose. Patients must additionally agree to refrain from
donating eggs during this period.
13. Signed and dated informed consent.
14. Patients willing and able to comply with scheduled visits, treatment plans, laboratory
tests, and other procedures.
15. Pre/peri-menopausal patients must be treated with GnRH agonist beginning at least 7
days prior to Day 1 of Cycle 1 and continuing every 28 days for the duration of study
treatment.
Exclusion Criteria:
1. Previous fulvestrant and CDK4/6 inhibitor (abemaciclib, palbociclib or ribociclib) in
any setting.
2. Prior use of AKT inhibitor (any setting).
3. History of malabsorption syndrome or other condition that would interfere with enteral
absorption or results in the inability or unwillingness to swallow pills.
4. Systemic chemotherapy within 14 days prior to study entry.
5. Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry.
6. Patients with known leptomeningeal disease, symptomatic brain metastases requiring
steroids, untreated brain metastases or spinal cord compression.
7. Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormality including any of the following:
1. History of angina pectoris, symptomatic pericarditis, coronary artery bypass
graft (CABG) or myocardial infarction within 12 months prior to study entry.
2. Known (documented) cardiomyopathy, i.e known left ventricular ejection fraction
(LVEF) < 50% (ECHO or MUGA not needed specifically for this trial).
3. History of symptomatic cardiac failure (NYHA class II-IV or LVEF <50%),
uncontrolled hypertension, cardiac dysrhythmia including atrial fibrillation
requiring medication, significant/symptomatic bradycardia, Long QT syndrome,
family history of idiopathic sudden death or congenital long QT syndrome or any
of the following:, cerebrovascular accident, or transient ischemic attack within
12 months; known risk factors for prolonged QT interval or Torsade's de Pointes;
Uncorrected hypomagnesaemia or hypokalaemia of Grade 3 or higher; Systolic Blood
Pressure (SBP) >160 mmHg or <90 mmHg; Bradycardia (heart rate <50 at rest), by
ECG (based on a mean of 3 ECGs) or pulse; On screening, QTcF >470 screening ECG
(based on a mean of 3 ECGs).
8. Pneumonitis, interstitial lung disease or pulmonary fibrosis.
9. Type I or II diabetes requiring insulin.
10. Use of drugs that are known potent cytochrome P450 3A inducers or inhibitors within 2
weeks or 5 elimination half-lives (whichever is longer) before the first dose of study
drug.
11. Known HIV or AIDS-related illness.
12. Active infection requiring systemic therapy.
13. Known positive HBV or HCV test indicating acute or chronic infection
1. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
(defined as having a negative HBsAg test and a positive hepatitis B core antibody
[HBcAb] test, accompanied by a negative HBV DNA test) are eligible.
2. Patients positive for HCV antibody are eligible only if polymerase chain reaction
(PCR) is negative for HCV RNA.
14. Clinically significant liver disease consistent with Child Pugh class B or C.
15. Administration of a live vaccine within 4 weeks prior to study entry.
16. Diagnosis of other malignancy within 5 years, except for adequately treated basal cell
or squamous cell skin cancer, or carcinoma in situ of the breast or cervix.
17. Participation in other studies involving investigational drug(s) within 4 weeks prior
to study entry and/or during study participation.
18. Persisting toxicity related to prior therapy >Grade 1 (except for stable peripheral
neuropathy grade 2 or alopecia grade 2).
19. Other severe acute or chronic medical condition, including colitis, inflammatory bowel
disease, psychiatric condition, recent or active suicidal ideation or behaviour, or
end stage renal disease on haemodialysis, or laboratory abnormality that may increase
the risk associated with study participation or investigational products
administration or may interfere with the interpretation of results and, in the
judgment of the Investigator, would make the patient inappropriate study entry.
20. Radiation therapy (other than palliative radiation to bony metastases) as cancer
therapy within 4 weeks prior to initiation of study treatment.
21. Palliative radiation to bony metastases within 2 weeks prior to initiation of study
treatment.
22. Allergy or hypersensitivity to components of the ipatasertib, palbociclib, or
fulvestrant.
23. Patients able to have children who are unwilling or unable to use 2 highly effective
method(s)¹ of contraception for the duration of the study and for at least 60 days
after the last dose of investigational product. Patient pregnant or breastfeeding.
24. Need for chronic corticosteroid therapy of >10 mg of prednisone per day or an
equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a
chronic disease.
