Nab-Paclitaxel and Pembrolizumab in Treating Patients with Hormone Receptor-Positive Breast Cancer before Surgery
- Participants must have histologically or cytologically confirmed invasive breast cancer
- Participants must have operable breast cancer, with tumors greater than or equal to 2 cm in size; participants must not have any evidence of distant metastatic disease; inflammatory breast cancer is permitted
- All confirmed invasive disease must have been tested for estrogen receptor (ER), progesterone receptor (PR), and HER2 and participants must have hormone receptor-positive, HER2-negative breast cancer (ER > 1% or PR > 1%, AND HER2-negative per American Society of Clinical Oncology [ASCO] College of American Pathologists [CAP] guidelines, 2013)
- Participants with multicentric, multifocal, and/or contralateral cancers are allowed as long as one lesion meets eligibility and no biopsied tumor is HER2+
- No prior chemotherapy, biologic therapy, hormonal therapy or investigational therapy for this operable breast cancer
- No prior radiation to the ipsilateral breast
- The participant has an Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Absolute neutrophil count >= 1500/mm^3
- Platelets >= 100,000/mm^3
- Hemoglobin >= 9 g/dL
- Total bilirubin =< 1.5 mg/dL (=< 2.0 in participants with known Gilbert’s syndrome)
- Serum creatinine =< 1.5 mg/dL OR calculated glomerular filtration rate (GFR) >= 60 mL/min
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 times the upper limit of normal
- International normalized ratio (INR) or prothrombin time (PT) < 1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT) < 1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- The participant is capable of understanding and complying with the protocol and has signed the informed consent document
- The participant must be willing to undergo the three required research biopsies over the course of protocol therapy; participants who undergo an attempted research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in order to continue on protocol
- The effects of pembrolizumab on the developing human fetus are unknown; for this reason, both women and men of child-bearing potential must agree to use adequate contraception starting with the first dose of study therapy and for the duration of study participation, through 120 days after the last dose of study medication; Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; while on the study, women may not breast-feed; women of childbearing potential are defined as those who have not been surgically sterilized or have not been free from menses for > 1 year
- Female subject of childbearing potential should have a negative urine or serum pregnancy test within 7 days prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Participants on bisphosphonates may continue receiving bisphosphonate therapy during study treatment
- The participant has received prior pembrolizumab or any other anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy, or has participated in any prior studies involving pembrolizumab
- Hypersensitivity to pembrolizumab or any of its excipients
- The participant has any history or evidence of active, non-infectious pneumonitis or interstitial lung disease
- The participant has an uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure (New York Heart Association class III or IV), active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, chronic liver or renal disease, or severe malnutrition
- Concurrent use of potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment with nab-paclitaxel
- Pregnant women are excluded from this study because pembrolizumab has the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab
- Active infection requiring intravenous antibiotics at week 1 day 1
- Individuals with a history of a second malignancy are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible 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; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and non-melanoma cancer of the skin; participants with other cancers diagnosed within the past 5 years and felt to be at low risk of recurrence should be discussed with the study sponsor to determine eligibility
- The participant has a medical condition that requires chronic systemic steroid therapy or any other form of immunosuppressive medication including disease modifying agents; replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- The participant has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
- The participant is known to be positive for hepatitis B surface antigen, or hepatitis C ribonucleic acid (RNA); testing for screening is not required
- Known human immunodeficiency virus (HIV)-positive participants; HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pembrolizumab; in addition, these participants are at increased risk of lethal infections with bone marrow suppressive therapy, i.e. nab-paclitaxel; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated; testing for screening is not required
- The participant has received a live vaccine within 28 days of planned start of study therapy * Note: seasonal influenza vaccines for infection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (i.e. Flu-Mist) are live attenuated vaccines, and are not allowed
I. To characterize changes in tumor cell PD-L1 expression after treatment with either nab-paclitaxel or pembrolizumab monotherapy.
I. To characterize changes in additional core peri-tumoral immune biomarkers ( stromal tumor infiltrating lymphocytes;  PD-1 expression;  PD-L2 expression;  CD8 expression) after treatment with either nab-paclitaxel or pembrolizumab monotherapy.
II. To characterize changes in peri-tumoral immune biomarkers ( stromal tumor infiltrating lymphocytes;  PD-1 expression;  PD-L1 expression;  PD-L2 expression;  CD8 expression) after treatment with either nab-paclitaxel or pembrolizumab monotherapy followed by nab-paclitaxel/pembrolizumab combination therapy (at the time of interval biopsy and definitive breast surgery).
III. To evaluate the safety and tolerability of combination nab-paclitaxel and pembrolizumab therapy in patients with hormone receptor-positive breast cancer treated in the neoadjuvant setting.
IV. To determine the rate of pathologic complete response (pCR) with combination nab-paclitaxel and pembrolizumab in the neoadjuvant setting.
V. To determine the overall response rate, based on radiographic assessment, with combination nab-paclitaxel and pembrolizumab in the neoadjuvant setting.
VI. To explore disease free-survival with combination nab-paclitaxel and pembrolizumab in the neoadjuvant setting.
VII. To explore whether levels of peri-tumoral immune biomarkers ( stromal tumor infiltrating lymphocytes;  PD-1 expression;  PD-L1 expression;  PD-L2 expression;  CD8 expression) in pre-treatment biopsies correlate with response to treatment as assessed by residual cancer burden (RCB) and pathologic complete response (pCR) at surgery.
VIII. To explore whether changes in peri-tumoral immune biomarkers ( stromal tumor infiltrating lymphocytes;  PD-1 expression;  PD-L1 expression;  PD-L2 expression;  CD8 expression) on serial biopsies and at surgery correlate with response to treatment as assessed by RCB and pCR.
CORRELATIVE SCIENCE OBJECTIVES:
I. To characterize an expanded set of immune markers (based on histology, protein expression, and messenger ribonucleic acid [mRNA] expression) in hormone receptor-positive breast tumors both pre-treatment and on serial biopsies, and to explore whether any members of this expanded set correlate with response to treatment.
II. To characterize the immune marker profile in peripheral blood mononuclear cells (PBMCs) both pre-treatment and on serial blood draws.
III. To explore whether levels of immune markers in the peripheral blood correspond with levels of immune biomarkers in peri-tumoral tissue, both pre-treatment and on therapy.
IV. To explore cell-free deoxyribonucleic acid (DNA) (cfDNA) in comparison to tumor specimens before and after immunotherapy.
V. To characterize the structure and function of the gut microbiome in patients with breast cancer prior to starting this clinical trial.
VI. To determine whether pre-treatment characteristics of the structure and function of the gut microbiome in patients with breast cancer is associated with response to treatment.
VII. To characterize changes in the structure and function of the gut microbiome of patients with breast cancer after exposure to nab-paclitaxel or pembrolizumab alone (after week 1 [W1] for both Arms).
VIII. To characterize changes in the structure and function of the gut microbiome of patients with breast cancer after exposure to nab-paclitaxel and pembrolizumab together (after week 4 [W4]).
IX. To determine whether changes in the overall diversity of the gut microbiome, estimated by the Shannon Index, of patients with breast after exposure to nab-paclitaxel or pembrolizumab alone (after W1 for both Arms) is associated with response to treatment.
X. To determine whether changes in the overall diversity of the gut microbiome, estimated by the Shannon Index, of patients with breast after exposure to nab-paclitaxel and pembrolizumab together (after W4).
XI. To determine if the abundance and functional profile of specific gut bacteria are associated with response to treatment.
XII. To evaluate the functional pathways that may play a role as a predictive biomarker of response to treatment.
OUTLINE: Patients are randomized to 1 of 2 cohorts.
COHORT A: Patients undergo research biopsies of the breast at baseline, post-monotherapy (end of 2 week run in), during doublet therapy (between weeks 6 and 7), and at the time of surgery. Patients receive nab-paclitaxel intravenously (IV) over 30 minutes on day 1 weekly for up to 12 weeks. Beginning week 3, patients receive pembrolizumab IV over 30 minutes on day 1 on weeks 3, 6, 9, 12, and 15.
COHORT B: Patients undergo research biopsies of the breast at baseline, post-monotherapy (end of 2 week run in), during doublet therapy (between weeks 6 and 7), and at the time of surgery. Patients receive pembrolizumab IV over 30 minutes on day 1 on weeks 1, 4, 7, 10, and 13. Beginning week 3, patients receive nab-paclitaxel IV over 30 minutes on day 1 weekly for up to 12 weeks.
In both cohorts, treatment continues in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 5 years.
Trial Phase Phase I
Trial Type Treatment
Dana-Farber Harvard Cancer Center
Sara Michell Tolaney
- Primary ID 16-466
- Secondary IDs NCI-2017-00399
- Clinicaltrials.gov ID NCT02999477