Palbociclib With Fulvestrant for Metastatic Breast Cancer After Treatment With Palbociclib and an Aromatase Inhibitor

In this phase II trial, the primary objective is to determine the progression-free survival
(PFS) of the cyclin dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib with fulvestrant in
women and men with estrogen or progesterone receptor (ER/PR) positive, HER2-negative
metastatic breast cancer (MBC) who progressed on treatment with palbociclib and an aromatase
inhibitor (AI). The study will also determine the prevalence rate of estrogen receptor α
(ESR1) and phosphatidylinositol-3-kinase (PI3K) mutations in the study population.

The secondary objectives include evaluating the progression-free survival (PFS) in
participants with and without ESR1 mutations, and PI3K mutations through analysis of tumor
biopsies and circulating plasma tumor DNA (ptDNA) samples. The study will also describe other
alterations in genes and gene products relevant to the cell cycle, drug targets, tumor
sensitivity and resistance, and identify novel protein kinases activated in biopsies from
participants with hormone refractory MBC who progressed on prior palbociclib and AI. The data
will be correlated with tumor subtypes, expression profiles, and candidate phosphoprotein
expression with PFS in the study population.

Inclusion Criteria:

- Women may be premenopausal or postmenopausal

- Metastatic or locally advanced breast cancer, not amenable to surgery or radiation
with curative intent

- ER-positive and/or PR-positive, HER2-negative tumor

- Prior treatment: progressed on and following at least 6 months of combined treatment
with palbociclib and AI therapy; up to one (1) prior line of chemotherapy for advanced
disease is allowed in addition to any number of prior lines of endocrine therapy; no
prior treatment with fulvestrant, everolimus, or any agent whose mechanism of action
is to inhibit the PI3K-mTOR pathway in the metastatic setting

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Evaluable or measurable disease

- Disease that is amenable to biopsy

- Adequate hematologic and renal function

- History of central nervous system metastasis is allowed if treated and stable

- Prior radiation therapy is allowed if recovered from toxicity and disease evaluable
for response outside of the radiation fields or evidence of post-radiation progression
of previously irradiated sites of disease

- Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

- Women who are pregnant or breast-feeding

- Concurrent use of inhibitors or inducers of CYP3A4, or medications which prolong the
QTc interval

- Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 2 weeks
before registration; prior radiotherapy to ≥25% of bone marrow are not eligible
independent of when it was received

- Any other malignancy within 3 years prior to registration, except for adequately
treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix

- Any severe cardiac event within 6 months of registration

- Prior hematopoietic stem cell or bone marrow transplantation

- Known abnormalities in coagulation such as bleeding diathesis, or treatment with
anticoagulants precluding intramuscular injections of fulvestrant or goserelin (if
applicable)

- Known or possible hypersensitivity to palbociclib, fulvestrant, goserelin (if
applicable) or to any of their excipients

- Known human immunodeficiency virus infection

- Other severe acute or chronic medical or psychiatric condition, including recent or
active suicidal ideation or behavior, or laboratory abnormality that may increase the
risk associated with study participation or investigational product administration or
may interfere with the interpretation of study results and, in the judgment of the
investigator, would make the patient inappropriate for entry into this study