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Palbociclib, Bosutinib, and Fulvestrant for the Treatment of Metastatic Hormone Receptor Positive and HER2 Negative Breast Cancer Refractory to Aromatase Inhibitors

Trial Status: Active

This trial studies the side effects and best dose of bosutinib and palbociclib when given together with fulvestrant in treating patients with hormone receptor positive and HER2 negative breast cancer that has spread to other places in the body (metastatic) and does not respond to aromatase inhibitor therapy (refractory to aromatase inhibitors). Bosutinib and palbociclib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells. This study is being done because it is not known if this combination therapy can be safely used at effective doses, preventing or postponing the need to start treatment with chemotherapy.

Inclusion Criteria

  • Signed informed consent obtained prior to any study specific assessments and procedures
  • Premenopausal and postmenopausal women
  • Biopsy proven diagnosis of estrogen receptor (ER) and/or progesterone receptor (PR) positive, HER2 negative, advanced breast cancer (locoregionally recurrent or metastatic disease), either from the primary or a metastatic site. * ER, PR and HER2 measurements should be performed according to institutional guidelines, in a Clinical Laboratory Improvement Act (CLIA)-approved setting. * Breast cancer is ER-positive and/or PR-positive tumor (>= 1% positive stained cells) based on local CLIA-certified laboratory results * HER2-negative breast cancer: ** Cut-off values for positive/negative staining should be in accordance with current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines. ** Patients with equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines are eligible, as long as they have not received and are not scheduled to receive anti-HER2 treatment.
  • A formalin-fixed paraffin-embedded (FFPE) tumor tissue block from diagnostic biopsy must be transmitted to MedStar Georgetown University Hospital Pathology Department repository and confirmation of receipt must be available prior to initiation of treatment on study
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Must have received no more than 3 lines of chemotherapy for the treatment of breast cancer in the metastatic setting and be progressive on at least one aromatase inhibitor and one CDK 4/6 inhibitor
  • Pregnancy must be ruled out * Serum or urine pregnancy test must be negative within 14 days of treatment start in women of childbearing potential. * Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before enrollment, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. * Patients may be considered postmenopausal in case that one of the following criteria applies: ** Prior bilateral oophorectomy, OR ** Age >= 60 years, OR ** Age < 60 years with intact uterus and amenorrhoeic for >= 12 consecutive months prior to chemotherapy and/or endocrine therapy exposure, OR ** Age < 60 years hysterectomized and follicle stimulating hormone (FSH) and plasma estradiol levels in the post-menopausal range according to local policies prior to chemotherapy and/or endocrine therapy exposure
  • Willingness to undergo adequate contraception if childbearing potential * Women of childbearing potential must use adequate contraception for the duration of protocol treatment and for 3 months after the last treatment with palbociclib/bosutinib * Adequate contraception is defined as one highly effective form (i.e. abstinence, [fe]male sterilization) OR two effective forms (e.g. non-hormonal intrauterine device [IUD] and condom / occlusive cap with spermicidal foam / gel / film / cream / suppository)
  • Patients must be able and willing to swallow and retain oral medication
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
  • Alkaline phosphatase =< 2.5 x ULN (=< 5.0 x ULN if bone metastases present)
  • Total serum bilirubin =< 1.5 x ULN
  • Serum creatinine within normal institutional limits or creatinine clearance >= 50 mL/min/1.73 m^2 for patients with serum creatinine levels above institutional ULN
  • Resolution of all acute toxic effects of prior therapy, including radiotherapy to grade =< 1 (except toxicities not considered a safety risk for the patient) and recovery from surgical procedures
  • Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
  • Patient has discontinued all previous therapies for cancer (including cytotoxic chemotherapy, targeted therapy [including, but not limited to, everolimus], radiotherapy, immunotherapy, and investigational therapy) for at least 14 days prior to receiving study drugs and recovered from the acute effects of therapy (treatment-related toxicity resolved to baseline) except for residual alopecia or peripheral neuropathy

Exclusion Criteria

  • Concurrent therapy with other investigational products
  • Current use of food or drugs known to be potent inhibitors or inducers of CYP3A4
  • Known hypersensitivity to fulvestrant, palbociclib or bosutinib, or to any of their excipients
  • Uncontrolled intercurrent illness including (active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, diabetes, pulmonary embolism in the past 6 months, or psychiatric illness/social situations that would limit compliance with study requirements)
  • Active uncontrolled or symptomatic brain metastases. Previously treated and clinically stable, as per investigator’s judgment, brain metastases are permitted
  • Unable to comply with study requirements
  • Presence of a condition that would interfere with enteric absorption of palbociclib/bosutinib
  • Pregnant women, or women of childbearing potential without a negative pregnancy test (serum or urine) within 14 days prior to starting treatment on study * Breastfeeding must be discontinued prior to study entry
  • Patients on combination antiretroviral therapy, i.e. those who are human immunodeficiency virus (HIV)-positive (potential for pharmacokinetic interactions or increased immunosuppression with palbociclib)
  • Patients with clinically significant history of liver disease, including viral or other known hepatitis, current alcohol abuse, or cirrhosis, etc.
  • Patients on chronic anticoagulation (fulvestrant is IM injection) with the exception of patients enrolling in dose level A2 (no fulvestrant)

District of Columbia

MedStar Georgetown University Hospital
Status: ACTIVE
Contact: Paula R Pohlmann
Phone: 202-444-2223


I. To determine the safety and tolerability of bosutinib monohydrate (bosutinib) when used in combination with palbociclib and fulvestrant in patients with advanced hormone receptor positive (HR+) metastatic breast cancer (MBC) who are refractory to aromatase inhibitors (AI) and CDK4/6 inhibitors.


I. To determine the anti-tumor effect of bosutinib when used in combination with palbociclib and fulvestrant in patients with advanced HR+MBC who are refractory to AI and CDK4/6 inhibitors.

II. To determine clinical pharmacology parameters of bosutinib in this regimen.

III. To build a tissue repository at the Georgetown Lombardi Comprehensive Cancer Center to obtain initial translational information.


I. To characterize changes in markers of unfolded protein response, autophagy, apoptosis, deoxyribonucleic acid (DNA) damage/repair, proliferation, and selected drug targets, e.g., CDK4/6, mTOR, AKT(P).

II. To describe the molecular profiling of baseline tumor specimen utilizing next generation sequencing (NGS).

III. To describe tumor specific mutations through the detection of plasma tumor DNA.

OUTLINE: This is a dose-escalation study of palbociclib and bosutinib.

Patients receive palbociclib orally (PO) once daily (QD) on days 1-21, and bosutinib PO daily on days 1-5, 8-12, 15-19, and 22-26. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive fulvestrant intramuscularly (IM) one in each buttock, on days 1, 15, 29, and once monthly thereafter in the absence of disease progression or unacceptable toxicity. Pre-menopausal patients also receive goserelin subcutaneously (SC) on day 1. Cycles with goserelin repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for 1 year.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
MedStar Georgetown University Hospital

Principal Investigator
Paula R Pohlmann

  • Primary ID STUDY00000057
  • Secondary IDs NCI-2019-06239
  • ID NCT03854903