Palbociclib, Everolimus, and Exemestane in Treating Patients with Estrogen Receptor Positive and HER2 Negative Metastatic Breast Cancer

Status: Closed to Accrual


This phase Ib / IIa trial studies the side effects and best dose of palbociclib and everolimus and how well they work when given together with exemestane in treating patients with estrogen receptor positive and human epidermal growth factor receptor 2 (HER2) negative breast cancer that has spread to other places in the body. Palbociclib, everolimus, and exemestane may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Participants with histologically or cytologically confirmed hormone receptor (HR)-positive, Her2-negative metastatic breast cancer; central confirmation of HR positivity is not required
  • Postmenopausal women as defined as: * Age > 60 years or * Age >= 45 with intact uterus and amenorrhea for >= 12 consecutive months or follicle stimulating hormone (FSH) levels within postmenopausal range according to the ranges established by the testing facility or * Premenopausal women who have been on a gonadotrophin releasing hormone (GnRH) agonist for at least 6 weeks prior to study entry; women in this group MUST remain on the GnRH agonist for the duration of protocol treatment or * Status post bilateral oophorectomy, after adequate healing post-surgery
  • Men are eligible, as long as on a GnRH agonist for at least 6 weeks prior to study entry; men MUST remain on the GnRH agonist for the duration of protocol treatment
  • Participants enrolled in the Phase I portion must have evaluable disease; participants enrolled in the Phase II portion must have measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Prior treatment specifics: * Participants must have radiological or objective evidence of progression to a CDK4/6 inhibitor regimen in the metastatic setting AND relapse/progression on an nonsteroidal anti-inflammatory drug (NSAI) (defined as either relapsed =< 12 months after completing adjuvant NSAI or progressed through an NSAI for metastatic or locally advanced breast cancer) * Participants may have received any number of previous endocrine/hormonal lines of therapy in the metastatic setting, as long none of them were exemestane-based and the last dose is >= 14 days prior to registration * Participants may have received any CDK4/6 inhibitor (i.e. palbociclib, ribociclib, abemacicliclib, etc) as long as the last dose is >= 14 days prior to registration * Participants may have received up to one prior chemotherapy line for advanced breast cancer as long as the last dose is >= 21 days prior to registration * Participants may have received prior biologic treatments or investigational drugs as long as the last dose is >= 21 days prior to registration * Participants may have received radiotherapy for palliative purposes but must not be experiencing > grade 1 treatment related toxicities and have completed treatment >= 14 days prior to registration
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • For participants enrolling the phase IIa part of the study, accessible tumor lesion(s) for the purpose of research biopsy and willingness to undergo a research biopsy before treatment initiation and at the time of disease progression, as well as a single research blood sample before initiation of therapy; participants who undergo an attempted on-treatment research biopsy and in whom inadequate tissue is obtained are still eligible to receive protocol therapy; they will not be required to undergo a repeat research biopsy attempt
  • For participants enrolling the phase Ib part of the study, willingness to provide archival tumor samples when available
  • Absolute neutrophil count >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • Total hemoglobin >= 9 g/dL (which may be post transfusion)
  • Total bilirubin =< 1.5 x institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase[(SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal or =< 5 x institutional upper limit of normal for participants with liver metastases
  • Creatinine =< 1.5 x above institutional normal or >= 60 ml/min/1.73 m^2 for subjects with creatinine levels above institutional normal
  • Baseline corrected QT (QTc) =< 500 ms
  • Fasting plasma glucose < 140 mg/dL/7.8 mmol/L
  • There will be no women of child-bearing potential in this study; if, for any reason, a woman should become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately; of note, premenopausal women and men are only eligible if they have been on a GnRH agonist for at least 6 weeks prior to study entry; these participants MUST remain on the GnRH agonist for the duration of protocol treatment; such participants should be counseled prior to study entry that GnRH agonists alone may not be adequate contraception and that adequate contraception (barrier method of birth control; abstinence) should be employed for the duration of study participation
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Participants who have demonstrated intolerance to 125 mg of palbociclib are ineligible for the phase I portion
  • Participants who are receiving any other investigational agents
  • Participants who have received previous treatment with a mammalian target of rapamycin (mTOR) inhibitor
  • Participants who have received prior treatment with exemestane in the metastatic setting or who have recurred within 12 months of adjuvant exemestane
  • Participants with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to palbociclib, everolimus or exemestane
  • Participants with known brain metastases may be enrolled in this study if radiation therapy and/or surgery have been completed with a minimum of 3 months of stable disease demonstrated on serial evaluation by computed tomography (CT) (with contrast enhancement) or magnetic resonance imaging (MRI); such participants must no longer require treatment with corticosteroids or enzyme inducing anti-epileptic medications for their central nervous system (CNS) disease
  • Participants with bilateral diffuse lymphangitic carcinomatosis
  • Participants with significant symptomatic deterioration of lung function; if clinically indicated, pulmonary function tests including measures of predicted lung volumes, carbon monoxide diffusing capability test (DLco), oxygen (O2) saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates
  • Evidence of current pneumonitis
  • Subjects with organ allograft requiring immunosuppression
  • Participants with uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; ability to comply with study requirements is to be assessed by each investigator at the time of screening for study participation * Impairment of gastrointestinal function or who have gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea or malabsorption syndrome)
  • Participants receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A within 7 days of registration; proton pump inhibitors (PPI) may be taken while on study, however it is recommended that the PPI is taken 12 hours from the time of palbociclib administration; if needed, alternative antacid therapies may be used including H2-receptor antagonists and locally acting antacids; H2-receptor antagonists should be administered with a staggered dosing regimen (twice daily); the dosing of palbociclib should occur at least 10 hours after H2-receptor antagonist evening dose and 2 hours before the H2-receptor antagonist morning dose
  • Pregnant women are excluded
  • Individuals with a history of a different malignancy are ineligible except for the following circumstances: a) if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; b) if diagnosed with the following cancers and treated within the past 5 years: ductal carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
  • Participants known to be human immunodeficiency virus (HIV)-positive on combination antiretroviral therapy are ineligible; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated; screening for HIV infection at baseline is not required

Locations & Contacts

See trial information on for a list of participating sites.

Trial Objectives and Outline


I. To describe the safety and tolerability and define maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of palbociclib in combination with everolimus and exemestane in participants with estrogen receptor (ER)+ Her2− advanced breast cancer. (Phase Ib)

II. To estimate the activity of palbociclib in combination with everolimus and exemestane, as defined by clinical benefit rate (CBR), in participants with ER+ Her2− advanced breast cancer. (Phase IIa)


I. To describe the pharmacokinetic (PK) profile of everolimus and palbociclib in the triple combination and evaluate the drug-drug interaction (DDI) potential (effect of palbociclib on the PK profile of everolimus). (Phase Ib)

II. To investigate biomarkers of sensitivity and resistance to CDK 4/6 inhibitors at the deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and protein levels respectively via whole exome sequencing, RNA sequencing (Seq) and immunohistochemistry of paired tumor biopsies. (Phase Ib and IIa)

III. To estimate the activity of palbociclib in combination with everolimus and exemestane, as defined by overall response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression free-survival (PFS) according to investigator assessment, in participants with ER+ Her2− advanced breast cancer. (Phase IIa)

OUTLINE: This is a phase Ib, dose-escalation study of palbociclib and everolimus followed by a phase IIa study.

Patients receive palbociclib orally (PO) once daily (QD) on days 1-21, everolimus PO QD on days 1-28, and exemestane PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and every 8 or 12 weeks.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type


Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Sara Michell Tolaney

Trial IDs

Primary ID 16-177
Secondary IDs NCI-2016-01367 ID NCT02871791