Clinical Trials

Inclusion Criteria: 

• ≥ 18 years of age.
• Pre- or postmenopausal women or men. Postmenopausal women are defined as:
  • 60 years of age with no vaginal bleeding over the prior year; or
  • < 60 years with "premature menopause" or "premature ovarian failure," which manifests itself with secondary amenorrhea for at least 1 year and follicle stimulating hormone (FSH) and estradiol levels in the postmenopausal range according to institutional standards; or
  • Surgical menopause with bilateral oophorectomy.
  • Note: Premenopausal women who meet all the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy. Testicular suppression (such as Lupron) can be used at the investigator's discretion.
• Every attempt should be made to obtain a biopsy of metastatic breast cancer tissue to provide histological or cytological confirmation ofER+/HER2- disease as assessed by a local laboratory, according to American Society of Clinical Oncology/College of American Pathologists guidelines, using slides, paraffin blocks, or paraffin samples. If a biopsy is done, it will also undergo genomic testing at some point to determine if an ESRl mutation is present. If a biopsy is not possible or inappropriate from a clinical standpoint, the ER and HER2 status from the tissue obtained at the time of the original metastatic diagnosis must confirm that the subject is ER+ and HER2-.
• Locally advanced and/or metastatic breast cancer with radiological or clinical evidence of progression on an Al in combination with either palbociclib or ribociclib as their first hormonal treatment for metastatic disease. Before starting study treatment, subjects should have stopped any CDKi for at least 14 days.
• No evidence of progression for at least 6 months on an AI/CDKl combination for advanced breast cancer.
• At least 1 or more ESRl point mutations in the ESRl ligand binding domain as assessed in cell-free ctDNA obtained from a blood or breast cancer tissue. Examples may include, but not be limited to, the mutations Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, and Y537N or other mutations known to induce protein changes to the ESRl binding domain. The ctDNA sample collection or tissue must be obtained within 90 days prior to randomization to determine eligibility and baseline.
  • Note: A prior genomic test confirming that the subject has an ESRl mutation can be used to determine eligibility if obtained within 90 days prior to randomization; however, an ESRl ctDNA blood sample must also be collected within 30 days of randomization for analysis in the Sponsor's chosen assay.
• Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1 [Eisenhauer, et al, 2009]) or non-measurable lesions.
• Subjects who may have received 1 cytotoxic chemotherapy regimen for metastatic disease and/or those who received 1 cytotoxic chemotherapy regimen in either the neo-adjuvant or adjuvant setting prior to entry into the trial can be enrolled but must be free of all chemotherapy acute toxicity excluding alopecia and Grade 2 peripheral neuropathy before study entry. A washout period of at least 21 days is required between last chemotherapy dose and entry into the study.
• Eastern Cooperative Oncology Group (ECOG) performance score of O or 1.
• Adequate organ function as shown by:
  • Absolute neutrophil count (ANC) :2:1,000 cells/mm^3 (2:1 g/L);
  • Platelet count :2:100 g/L cells/mm^3 (2:100 g/L);
  • Hemoglobin :2:8.0 g/dl (80 g/L);
  • ALT and AST levels::S3 upper limit of normal (ULN) or ::S5 in the presence of liver metastasis;
  • Total serum bilirubin ::Sl .5 X ULN (::S3 X ULN for subjects known to have Gilbert Syndrome);
  • Alkaline phosphatase level ::S3 ULN;
  • Creatinine clearance of 40 mL/min or greater as calculated by the Cockcroft-Gault formula or by a standard method used by the investigational site.
• Able to swallow tablets.
• Able to understand and voluntarily sign a written informed consent before any screening procedures.

Exclusion Criteria:

• Lymphangitic carcinomatosisinvolving the lung.
• Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.
• Presence of brain metastasis.
• Prior progression of disease on fulvestrant, or other SERD therapy.
• Radiotherapy within 30 days prior to Visit O (Day 1) 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 Visit O (Day 1). Subjects must have recovered from radiotherapy toxicities prior to Visit O (Day 1).
• Known RB1 mutations or deletions that in the opinion of the investigator confer resistance to CDK4/6i. (Screening for RBI mutation is not required for entry.).
• History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of > 480 msec.
• History of a PE, DVT, or any known thrombophilia.
• On concomitant strong CYP3A4 inhibitors such as clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir.
• On strong and moderate CYP3A4 inducers such as amprenavir, barbiturates, carbamazepine, clotrimazole, dexamethasone, efavirenz, ethosuximide, griseofulvin, modafinil, nevirapine, oxcarbazepine, phenobarbital, phenytoin, chronic prednisone treatment, primidone, rifabutin, rifampin, rifapentine, ritonavir, or topiramate.
• Any significant co-morbidity that would impact the study or the subject's safety. Since the occurrence of interstitial lung disease (ILD) has been reported with CDKl, subjects with a history of ILD and those with severe dyspnea at rest or requiring oxygen therapy should not enter the study.
• Active systemic bacterial or fungal infection (requiring intravenous [IV] antibiotics at the time of initiating study treatment).
• History of a positive human immunodeficiency virus (HIV) or hepatitis B virus (HBV) test. Screening is not required for enrollment.
• Hepatitis C virus (HCV) at Screening who still have a viral load. Subjects previously treated and achieved HCV cure (no viral load) can be entered into the study.
• 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.
• Positive serum pregnancy test (only if premenopausal).
• Sexually active premenopausal women and men unwilling to use contraception.
• Women who are breast feeding.
• History of non-compliance to medical regimens.
• Unwilling or unable to comply with the protocol.
• Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 1/30/24. Questions regarding updates should be directed to the study team contact.