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Pembrolizumab, Letrozole, and Palbociclib in Treating Patients With Stage IV Estrogen Receptor Positive Breast Cancer With Stable Disease That Has Not Responded to Letrozole and Palbociclib

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2017 by City of Hope Medical Center
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center Identifier:
First received: May 18, 2016
Last updated: April 13, 2017
Last verified: April 2017
This phase II trial studies how well pembrolizumab works when given together with letrozole and palbociclib in patients with stage IV estrogen receptor positive breast cancer with stable disease that has not responded to letrozole and palbociclib. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Estrogen can cause the growth of breast cancer cells. Antihormone therapy, such as letrozole, may lessen the amount of estrogen made by the body. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab, letrozole, and palbociclib may be an effective treatment for patients with stage IV estrogen receptor positive breast cancer.

Condition Intervention Phase
Estrogen Receptor Positive
HER2/Neu Negative
Recurrent Breast Carcinoma
Stage IV Breast Cancer
Other: Laboratory Biomarker Analysis
Drug: Letrozole
Drug: Palbociclib
Biological: Pembrolizumab
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase II Study of the Addition of MK-3475 (Pembrolizumab) to Letrozole and Palbociclib in Patients With Metastatic Estrogen Receptor Positive Breast Cancer Who Have Stable Disease But Are Not Responding to Letrozole and Palbociclib

Resource links provided by NLM:

Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Response rate (CR or PR) assessed using RECIST version 1.1 [ Time Frame: Up to 24 months ]

Secondary Outcome Measures:
  • Clinical Benefit Response assessed using RECIST version 1.1 [ Time Frame: Up to 24 months ]
  • Duration Of Response assessed using RECIST version 1.1 [ Time Frame: Up to 24 months ]
  • Incidence of adverse events assessed by NCI CTCAE, version 4 [ Time Frame: Up to 24 months ]
    Adverse events will be analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. Immune-related adverse events will also be collected.

  • Overall Survival assessed using RECIST version 1.1 [ Time Frame: Up to 24 months ]
    Generated using Kaplan-Meier estimates.

  • Progression Free Survival assessed using RECIST version 1.1 [ Time Frame: Up to 24 months ]
    Generated using Kaplan-Meier estimates.

  • Time to treatment failure assessed using irRECIST [ Time Frame: Up to 24 months ]
    Generated using Kaplan-Meier estimates

Other Outcome Measures:
  • Clinical benefit assessed using irRECIST [ Time Frame: Up to 24 months ]
  • Tumor response assessed using irRECIST [ Time Frame: Up to 24 months ]

Estimated Enrollment: 18
Actual Study Start Date: September 30, 2016
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (letrozole, palbociclib, pembrolizumab)
Patients receive letrozole PO QD on days 1-28 and palbociclib PO QD for 3 weeks. Courses with letrozole and palbociclib repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Courses with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Letrozole
Given PO
Other Names:
  • CGS 20267
  • Femara
Drug: Palbociclib
Given PO
Other Names:
  • Ibrance
  • PD-0332991
  • PD-332991
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Detailed Description:


I. To evaluate the objective response rate (ORR), based on Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1), of pembrolizumab in combination with letrozole and palbociclib in patients with metastatic estrogen receptor (ER)+human epidermal growth factor receptor (HER)2- breast cancer, and determine if the addition of pembrolizumab in patients with stable disease (SD) on letrozole and palbociclib can achieve a response (complete response [CR], partial response [PR], and ORR) measured from the study baseline, based on RECIST version 1.1.


I. To determine the safety and tolerability of adding pembrolizumab (200 mg every 3 weeks) to ongoing treatment with letrozole (2.5 mg) and palbociclib (3 weeks on, one week off: dose of palbociclib can vary secondary to individual patient tolerance, range 75-125 mg) in patients with metastatic ER+HER2- breast cancer.

II. To evaluate progression-free survival (PFS). III. To evaluate overall survival (OS). IV. To evaluate duration of response (DOR) using RECIST version 1.1. V. To evaluate clinical benefit rate (CBR) using RECIST version 1.1. VI. To evaluate toxicities (using the National Cancer Institute [NCI] Common Terminology Criteria for adverse Events [CTCAE], version 4.0) associated with the triple drug combination (pembrolizumab, letrozole, and palbociclib) in patients with metastatic ER+HER2- breast cancer.

VII. To evaluate CR, PR, ORR, PFS, DOR, and CBR using immune-related Response Criteria In Solid Tumors (irRECIST); time to treatment failure will also be assessed.


I. To study cellular/humoral immune response by analyzing immune and stromal cell characteristics before and after treatment that correlate with clinical response; this includes programmed cell death 1 ligand 1 (PD-L1) expression levels.

II. To study the peripheral serum thymidine kinase (TK) level and its association with treatment response.

III. To study circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and the effect of combining pembrolizumab, letrozole, and palbociclib on ctDNA profiles.


Patients receive letrozole orally (PO) once daily (QD) on days 1-28 and palbociclib PO QD for 3 weeks. Courses with letrozole and palbociclib repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Courses with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 6 months for 3 years, and then every 12 months for 1 year.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Willing and able to provide written informed consent/assent for the trial
  • Willing and able to comply with all aspects of the treatment protocol
  • Postmenopausal women defined by at least one of the following criteria:

    • Prior bilateral oophorectomy OR amenorrheic for >= 12 months (if =< 55 years of age and prior to chemotherapy, or on medical ovarian ablative therapy, or received ovarian radiation for ablation in the past 5 years, and/or tamoxifen, or an aromatase inhibitor (AI) within the past year, then follicle stimulating hormone (FSH) and estradiol must be in the post-menopausal range and obtained within 28 days prior to registration OR;
    • Previous hysterectomy with one or both ovaries left in place (previous hysterectomy in which documentation of bilateral oophorectomy is unavailable AND FSH values consistent with the institutional normal values for the post-menopausal state; FSH levels must be obtained within 28 days prior to registration)
  • Presence of measurable disease meeting the following criteria: at least 1 lesion of > 10 mm in long axis diameter for non-lymph nodes or > 15 mm in short axis diameter for lymph nodes that is serially measurable according to RECIST version 1.1 using computerized tomography, magnetic resonance imaging, or panoramic and close-up color photography
  • Stage IV metastatic ER+HER2- breast cancer histologically proven per current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
  • Life expectancy of >= 3 months
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1
  • Patients must have been undergoing treatment with letrozole and palbociclib for >= 6 months with SD per RECIST version 1.1 and have tumors that have ceased to decrease (up to 20% of tumor growth allowed); patients who initially achieved best response as PR by ceased to continue to decrease and became SD (based on the PR nadir) during later courses are eligible (6 months SD disease)
  • Received 0-3 lines of previous therapy including endocrine and/or chemotherapy in advanced setting prior to initiation of letrozole plus palbociclib
  • Resolution of >= grade 2 toxicities of most recent therapy except for stable sensory neuropathy (=< grade 2) neutropenia (=< grade 2) and alopecia
  • Willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up-to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the study principal investigator (PI)
  • Absolute neutrophil count (ANC) >= 1,000 /mcL
  • Platelets >= 100,000 /mcL
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN
  • Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
  • Albumin >= 2.5 mg/dL
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN 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 X ULN unless subject is receiving anticoagulant therapy as along as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours 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
  • Female subjects of childbearing potential should be willing to use two methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year

Exclusion Criteria:

  • Patients currently participating and receiving study therapy or who have participated in a study of an investigational agent and received study therapy or used and investigational device within 4 weeks of the first dose of treatment
  • Previously received pembrolizumab or other anti-programmed cell death-1 (PD-1) or anti-PD-L1 immunotherapy
  • Does not have measurable disease per RECIST 1.1
  • Currently responding to letrozole and palbociclib with recent restaging imaging showing CR or PR (by RECIST, version 1.1)
  • Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
  • Known history of active TB (Bacillus tuberculosis)
  • Hypersensitivity to pembrolizumab or any of its excipients
  • Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or has not recovered (i.e., =< grade 1 or at baseline) for adverse events (AEs) due to agents administered > 4 weeks earlier
  • Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to stay day 1 or has not recovered (i.e. =< grade 1 or at baseline) from AEs due to a previously administered agent

    • Note: Patients with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
    • Note: If patient received major surgery, she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
  • Known active central nervous system (CNS) metastases and/or carcinomatous meningitis; patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability
  • Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs); 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
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • History of interstitial lung disease
  • Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
  • Active infection requiring systemic therapy
  • History of significant cardiovascular disease, defined as: congestive heart failure greater than New York Heart Association (NYHA) class II according to the NYHA functional classification; unstable angina or myocardial infarction within 6 months of enrollment; or serious cardiac arrhythmia
  • Clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT/corrected QT (QTc) ([QT interval/corrected QT interval], e.g., a repeated demonstration of a QTc interval > 480 ms), a family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes (TdP)
  • Concurrent use of drugs that are known to be moderate or strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or inducers or drugs that are known to prolong the QT interval
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interests of the patient to participate, in the opinion of the treating investigator
  • Pregnant or breastfeeding, or expecting to conceive children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Received a live vaccine within 30 days of planned start of study therapy; * Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02778685

United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Yuan Yuan, MD, PhD    800-826-4673      
Principal Investigator: Yuan Yuan, MD, PhD         
City of Hope Antelope Valley Recruiting
Lancaster, California, United States, 93534
Contact: Suzanne Branch    626-256-4673 ext 25648      
Sub-Investigator: Nimit Sudan, MD         
City of Hope Rancho Cucamonga Recruiting
Rancho Cucamonga, California, United States, 91730
Contact: Valerie Estala    626-256-4673 ext 81699      
Sub-Investigator: Benham Ebrahimi, MD         
City of Hope South Pasadena Recruiting
South Pasadena, California, United States, 91030
Contact: Odessa Rodriguez    626-256-4673 ext 81409      
Sub-Investigator: Christina Yeon, MD         
City of Hope West Covina Recruiting
West Covina, California, United States, 91790
Contact: Mei Zheng    626-256-4673 ext 81336      
Sub-Investigator: Gargi Upadhyaya, MD         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Principal Investigator: Yuan Yuan, MD, PhD City of Hope Medical Center
  More Information

Responsible Party: City of Hope Medical Center Identifier: NCT02778685     History of Changes
Other Study ID Numbers: 16058
NCI-2016-00694 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
16058 ( Other Identifier: City of Hope Medical Center )
Study First Received: May 18, 2016
Last Updated: April 13, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Estrogen Antagonists
Hormone Antagonists processed this record on May 25, 2017