Pembrolizumab, Letrozole, and Palbociclib in Treating Postmenopausal Patients With Newly Diagnosed Metastatic Stage IV Estrogen Receptor Positive Breast Cancer

Tracking Information
First Submitted Date ICMJE	May 18, 2016
First Posted Date ICMJE	May 20, 2016
Last Update Posted Date	April 25, 2018
Study Start Date ICMJE	September 30, 2016
Estimated Primary Completion Date	September 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: May 19, 2016)	Response rate (CR or PR) assessed using RECIST version 1.1 [ Time Frame: Up to 24 months ]
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT02778685 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: June 27, 2017)	Complete response rate 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
Original Secondary Outcome Measures ICMJE; (submitted: May 19, 2016)	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
Current Other Outcome Measures ICMJE; (submitted: May 19, 2016)	Clinical benefit assessed using irRECIST [ Time Frame: Up to 24 months ]; Tumor response assessed using irRECIST [ Time Frame: Up to 24 months ]
Original Other Outcome Measures ICMJE	Same as current
Descriptive Information
Brief Title ICMJE	Pembrolizumab, Letrozole, and Palbociclib in Treating Postmenopausal Patients With Newly Diagnosed Metastatic Stage IV Estrogen Receptor Positive Breast Cancer
Official Title ICMJE	Phase II Study of the Combination of Pembrolizumab, Letrozole and Palbociclib in Postmenopausal Patients With Newly Diagnosed Metastatic Estrogen Receptor Positive Breast Cancer
Brief Summary	This phase II trial studies how well pembrolizumab works when given together with letrozole and palbociclib in treating postmenopausal patients with newly diagnosed stage IV estrogen receptor positive breast cancer that has spread to other parts of the body. 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.
Detailed Description	PRIMARY OBJECTIVES: 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 newly diagnosed metastatic estrogen receptor (ER)+human epidermal growth factor receptor (HER)2- breast cancer, and determine if the addition of pembrolizumab to letrozole and palbociclib combination can achieve an improved response rate (ORR = complete response [CR] + partial response [PR]) measured from the study baseline, based on RECIST version 1.1. SECONDARY OBJECTIVES: I. To determine the safety and tolerability of adding pembrolizumab (200 mg every 3 weeks) to letrozole (2.5 mg) and palbociclib (125 mg 3 weeks on, one week off) in patients with metastatic ER+HER2- breast cancer. II. To evaluate the CR rate. III. To evaluate progression-free survival (PFS). IV. To evaluate overall survival (OS). V. To evaluate duration of response (DOR) using RECIST version 1.1. VI. To evaluate clinical benefit rate (CBR) using RECIST version 1.1. VII. 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. VIII. 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. TERTIARY OBJECTIVES: 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. IV. To evaluate genomic and phenotypic status of breast tumor. OUTLINE: 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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Estrogen Receptor Positive; HER2/Neu Negative; Postmenopausal; Recurrent Breast Carcinoma; Stage IV Breast Cancer
Intervention ICMJE	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
Study Arms	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.; Interventions: Other: Laboratory Biomarker Analysis; Drug: Letrozole; Drug: Palbociclib; Biological: Pembrolizumab
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Recruiting
Estimated Enrollment ICMJE; (submitted: June 27, 2017)	22
Original Estimated Enrollment ICMJE; (submitted: May 19, 2016)	18
Estimated Study Completion Date	September 2018
Estimated Primary Completion Date	September 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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; 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; *Newly diagnosed (cohort 2) stage IV metastatic ER+HER2- breast cancer histologically proven per current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines; allow up to 30 days prior use of endocrine therapy +/- CDK4/6 inhibitors for treatment of metastatic ER+ breast cancer; Life expectancy of >= 3 months; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2; 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; *Cohort 1 (accrual to 6 patients) is for patients who had ongoing stable disease (SD) on letrozole + palbociclib, enrolled on prior version of eligibility criteria to receive pembrolizumab after obtaining stable disease on letrozole + palbociclib; these patients must have been on treatment with letrozole and palbociclib for 6 months with SD per RECIST 1.1; received up to 3 lines of previous therapy including endocrine and/or chemotherapy in advanced setting prior to initiation of letrozole and palbociclib; no grade 3 toxicities except alopecia 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; For cohort 2, received > 30 days of prior treatment with endocrine therapy +/- CDK4/6 inhibitors before screening (letrozole is allowed for prior adjuvant endocrine therapy); 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
Sex/Gender	Sexes Eligible for Study: Female
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02778685
Other Study ID Numbers ICMJE	16058; NCI-2016-00694 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 16058 ( Other Identifier: City of Hope Medical Center )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	City of Hope Medical Center
Study Sponsor ICMJE	City of Hope Medical Center
Collaborators ICMJE	National Cancer Institute (NCI)
Investigators ICMJE	Principal Investigator: Yuan Yuan, MD, PhD City of Hope Medical Center
PRS Account	City of Hope Medical Center
Verification Date	April 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP