This is an open label, randomized, multicenter study evaluating the activity of lasofoxifene
relative to fulvestrant for the treatment of postmenopausal women with locally advanced or
metastatic ER+/HER2− breast cancer with an acquired ESR1 mutation and who have disease
progression on an aromatase inhibitor (AI) in combination with a cyclin dependent kinase
(CDK) 4/6 inhibitor.
The primary objective is to evaluate the progression free survival (PFS) of 5 mg lasofoxifene
relative to fulvestrant for the treatment of postmenopausal women with locally advanced or
metastatic estrogen receptor positive (ER+)/human epidermal growth factor 2 negative (HER2−)
breast cancer with an ESR1 mutation.
The secondary objectives are to evaluate:
1. Clinical benefit rate (CBR) and Objective Response Rate (ORR)
2. Duration of response
3. Time to response
4. Overall Survival (OS)
5. Pharmacokinetics of lasofoxifene
6. Quality of life (QoL)
7. Safety of lasofoxifene
8. Response to various ESR1 mutation subtypes
9. The presence of the following mutations from tumor free DNA will be documented and part
of an exploratory analysis:
1. erbb2 extracellular domain mutation 5310;
2. erbb2 kinase domain mutations V777, L755, and Exon 20 insertion;
3. all NF1 mutations that are truncating, frame shifting and nonsense or homozygous
deletions; and
4. KRAS.
Lasofoxifene is a potent SERM that has demonstrated in non-clinical models to prevent and
treat breast cancer. In a large clinical osteoporosis trial, lasofoxifene reduced the
incidence of ER+ breast cancer, which most likely represents a beneficial effect on
clinically undetectable breast cancer. The clinical and non-clinical results are not
unexpected based on the results seen with tamoxifen and fulvestrant as the mechanisms of
action are similar. Moreover, the safety profile of lasofoxifene is well established in
postmenopausal women and therefore a clinical trial investigating lasofoxifene for the
treatment of breast cancer is scientifically justifiable.
Subjects with ESR1 mutations have endocrine resistance and shorter time to progression when
treated with currently approved endocrine therapy. There is an unmet medical need for
endocrine agents that can provide greater efficacy in this population. Non-clinical in vitro
and in vivo studies with lasofoxifene have demonstrated efficacy. If this benefit translates
to subjects with ESR1 mutated breast cancer cells, an important treatment option beyond
fulvestrant will be available.
The population being recruited in this trial are subjects with advanced breast cancer who
have been treated with an AI in combination with a cycline dependent kinase (CDK) 4/6
inhibitor and who have an ESR1 mutation. The efficacy of endocrine agents in this population
has never been prospectively studied. For this reason, this study will evaluate lasofoxifene
in a randomized Phase 2 trial against a comparator to better evaluate the magnitude of the
effect as well as to provide data to estimate the Phase 3 sample size.
In both non-clinical and clinical studies, fulvestrant has shown activity in ESR1 mutated
breast cancer cells and will be used as the comparator in this Phase 2 study to better
determine the relative clinical efficacy of lasofoxifene. The FDA approved fulvestrant dose
will be used.
A major limiting factor in the administration of fulvestrant is its poor solubility requiring
IM injection. The volume of administration limits the dose that can be administered. Initial
clinical trials administered 250 mg of fulvestrant in 5 cc of castor oil as a single
injection once monthly. Because the IM injections were well tolerated, loading and higher
doses were investigated. This was found to have acceptable tolerability and resulted in
greater efficacy. Limited by the volume of administration higher doses of fulvestrant cannot
be investigated further.
Once the subject has consented to participate in the study, screening tests will be performed
within 30 days of enrollment.
All subjects meeting the eligibility criteria will be first stratified into those with
visceral metastasis and those without visceral metastasis. Each of these stratified groups
will then be further stratified into those with the Y537S ESR1 mutation and those without
this particular mutation. Each of the stratified groups will then be randomized 1:1 to
receive either 5 mg/d of oral lasofoxifene or fulvestrant 500 mg intramuscular (IM) Day 1,
15, and 29, then every 4 weeks thereafter. Treatment will continue until radiographic or
clinical evidence of disease progression. Enrolled subjects will be seen every 2 weeks for
the first month of treatment and then monthly until progression. Efficacy assessments will be
done every 8 weeks.
Inclusion Criteria:
1. Postmenopausal women defined as:
1. >/= 60 years of age with no vaginal bleeding, or
2. <60 years with amenorrhea for at least 1 year and follicle stimulating hormone
(FSH) and estradiol levels in the postmenopausal range according to institutional
standards, or
3. surgical menopause with bilateral oophorectomy.
2. If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide
histological or cytological confirmation of ER+/HER2− disease as assessed by a local
laboratory, according to ASCO/CAP guidelines, using slides, paraffin blocks, or
paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue
obtained at the time of the original diagnosis must confirm that the subject is ER+
and HER2−.
3. Locally advanced or metastatic breast cancer with radiological or clinical evidence of
progression on an AI in combination with a CDK 4/6 inhibitor for advanced breast
cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or
progression after at least 12 months of treatment in the metastatic setting).
4. Locally advanced or metastatic breast cancer with either measurable (according to
RECIST 1.1) or non-measurable lesions.
5. At least one or more of the following ESR1 mutations as assessed in tumor free DNA
obtained from a blood sample: Y537S, Y537N, Y537C, D538G, L536, E380Q, or S463P. This
assessment must be done within 30 days and available prior to randomization.
6. Received one chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to
entry into the trial but must be free of all chemotherapy toxicity before study entry.
7. ECOG performance score of 0 or 1.
8. Adequate organ function as shown by:
1. absolute neutrophil count (ANC) >/=1,500 cells/mm3
2. platelet count ≤100,000 cells/mm3
3. hemoglobin >/=9.0 g/dl
4. ALT and AST levels ≤2.5 upper limit of normal (ULN) or ≤5 in the presence of
visceral metastasis
5. total serum bilirubin ≤1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert
Syndrome)
6. alkaline phosphatase level ≤ 2.5 X ULN
7. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault
formula
8. International normalized ratio (INR), activated partial thromboplastin (aPTT), or
partial thromboplastin time (PTT) <2.0 X ULN.
- Able to swallow tablets.
- Able to understand and voluntarily sign a written informed consent before
any screening procedures.
Exclusion Criteria:
1. Prior use of any SERM (eg, tamoxifen, raloxifene, ospemifene, droloxifene, toremifene,
bazedoxifene, endoxifen, etc.) in the adjuvant or metastatic setting except for
subjects who completed adjuvant tamoxifen treatment and relapsed at least 1 year after
stopping tamoxifen and were then given an AI in combination with a CDK 4/6 inhibitor.
Prior use of raloxifene for osteoporosis, ospemifene for vulvo- vaginal atrophy, or
conjugated estrogens/bazedoxifene for hot flashes is allowed as long as the medication
had been stopped at the time of the subject being diagnosed with breast cancer.
2. Prior use of everolimus or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors.
3. Presence of brain metastasis.
4. Lymphangitic carcinomatosis involving the lung.
5. Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the
investigator.
6. Radiotherapy within 30 days prior to randomization except in case of localized
radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which
can then be completed within 7 days prior to randomization. Subjects must have
recovered from radiotherapy toxicities prior to randomization.
7. History of long QTC syndrome or a QTC of >480 ms.
8. History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6
months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance
are eligible as long as the DVT and/or PE occurred >6 months prior to enrollment and
there is no evidence for active thrombosis. The use of low dose ASA is permitted.
9. Any significant co-morbidity that would impact the study or the subject's safety.
10. History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
hepatitis C virus (HCV) at Screening.
11. History of malignancy within the past 5 years (excluding breast cancer), except basal
cell or squamous cell carcinoma of the skin curatively treated by surgery, or early
stage cervical cancer.
12. History of vaginal bleeding over the last year.
13. Uncontrolled hypertension defined as sitting systolic pressure >160 mm Hg or diastolic
pressure >100 mm Hg at Screening.
14. History of non-compliance to medical regimens.
15. Unwilling or unable to comply with the protocol.
16. Current participation in any clinical research trial involving an investigational drug
or device within the last 30 days.
