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

NCT02778685 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 3 other identifiers: 16058NCI-2016-00694P30CA033572
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 7

Brief Summary

This phase II trial studies how well pembrolizumab works when given together with endocrine therapy 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 (metastatic). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Estrogen can cause the growth of breast cancer cells. Fulvestrant blocks the use of estrogen by the tumor cells. Letrozole lowers the amount of estrogen made by the body. This may help stop the growth of tumor cells that need estrogen to grow. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab, palbociclib, and letrozole or fulvestrant may be an effective treatment for patients with stage IV estrogen receptor positive breast cancer.

Conditions

Metastatic Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7

Outcome Measures

Primary Outcomes (1)

• Response Rate (Complete Response or Partial Response)

  Assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Response rate was defined as the proportion of patients who had a partial or complete response to therapy.

  Up to 36 months

Secondary Outcomes (6)

• Incidence of Adverse Events

  Adverse events (Grade 2 or higher) were assessed from the time of initial treatment until discontinuation of treatment, up to 30 days. SAEs and irAEs were collected for 90 days after the end of study treatment.

• Complete Response Rate

  Up to 36 months

• Duration of Response

  Up to 36 months. Time from documentation of tumor response to disease progression or death

• Progression Free Survival

  Up to 36 months. From start of treatment to time of progression or death, whichever occurs first.

• Overall Survival

  Up to 36 months. From start of treatment to time of death.

Other Outcomes (1)

• Clinical Benefit

  Up to 36 months

Study Arms (3)

Cohort 3 (Patients start Palbo+Letro on Day -28; pembro added on C1D1)

EXPERIMENTAL

Patients receive either letrozole PO QD on days -28 to -1 and days 1-28, or fulvestrant on days -28, -14, and day 1 of subsequent cycles. Patients also receive palbociclib PO QD for 3 weeks. Cycles with palbociclib, and letrozole or fulvestrant repeat every 28 days in the absence disease progression or unacceptable toxicity. Patients also receive pembrolizumab IV over 30 minutes on day 1. Cycles with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Fulvestrant; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Drug: Palbociclib; Biological: Pembrolizumab

Cohorts 2 (Patients start letrozole + palbociclib + pembrolizumab as upfront therapy on C1D1)

EXPERIMENTAL

Patients receive letrozole PO QD on days 1-28 and palbociclib PO QD for 3 weeks. Cycles 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. Cycles with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Fulvestrant; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Drug: Palbociclib; Biological: Pembrolizumab

Cohorts 1 (letrozole + palbociclib) on C1D1 and add pembrolizumab after 6 months

EXPERIMENTAL

Patients receive letrozole PO QD on days 1-28 and palbociclib PO QD for 3 weeks. Cycles with letrozole and palbociclib repeat every 28 days in the absence of disease progression or unacceptable toxicity. \^ months later, patients also receive pembrolizumab IV over 30 minutes on day 1. Cycles with pembrolizumab repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Fulvestrant; Other: Laboratory Biomarker Analysis; Drug: Letrozole; Drug: Palbociclib; Biological: Pembrolizumab

Interventions

Fulvestrant DRUG

Also known as: Faslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780, ZD9238

Cohort 3 (Patients start Palbo+Letro on Day -28; pembro added on C1D1); Cohorts 1 (letrozole + palbociclib) on C1D1 and add pembrolizumab after 6 months; Cohorts 2 (Patients start letrozole + palbociclib + pembrolizumab as upfront therapy on C1D1)

Laboratory Biomarker Analysis OTHER

Correlative studies

Cohort 3 (Patients start Palbo+Letro on Day -28; pembro added on C1D1); Cohorts 1 (letrozole + palbociclib) on C1D1 and add pembrolizumab after 6 months; Cohorts 2 (Patients start letrozole + palbociclib + pembrolizumab as upfront therapy on C1D1)

Letrozole DRUG

Given PO

Also known as: CGS 20267, Femara

Cohort 3 (Patients start Palbo+Letro on Day -28; pembro added on C1D1); Cohorts 1 (letrozole + palbociclib) on C1D1 and add pembrolizumab after 6 months; Cohorts 2 (Patients start letrozole + palbociclib + pembrolizumab as upfront therapy on C1D1)

Palbociclib DRUG

Given PO

Also known as: 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one, Ibrance, PD 0332991, PD 332991, PD 991, PD-0332991

Cohort 3 (Patients start Palbo+Letro on Day -28; pembro added on C1D1); Cohorts 1 (letrozole + palbociclib) on C1D1 and add pembrolizumab after 6 months; Cohorts 2 (Patients start letrozole + palbociclib + pembrolizumab as upfront therapy on C1D1)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Cohort 3 (Patients start Palbo+Letro on Day -28; pembro added on C1D1); Cohorts 1 (letrozole + palbociclib) on C1D1 and add pembrolizumab after 6 months; Cohorts 2 (Patients start letrozole + palbociclib + pembrolizumab as upfront therapy on C1D1)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to provide written informed consent/assent for the trial
• Men or women \>= 18 years of age on day of signing informed consent
• Willing and able to comply with all aspects of the treatment protocol
• Postmenopausal patients 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 follicle stimulating hormone \[FSH\] 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; allow up to 30 days prior use of CDK4/6 inhibitors and up to 60 days of letrozole or other aromatase 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 and day -28 for cohort 3; 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)
• For Cohort 3, willing to undergo tumor biopsies at baseline (within 6 weeks of study onset), cycle 2 day 1 (C2D1) (+/-1 week) and at time-of-progression or end-of-treatment when feasible
• Absolute neutrophil count (ANC) \>= 1,000 /mcL (performed within 10 days of treatment initiation)
• Platelets \>= 100,000 /mcL (performed within 10 days of treatment initiation)
• Hemoglobin \>= 9 g/dL or \>= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 10 days of treatment initiation)

You may not qualify if:

• 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 CDK4/6 inhibitors or \> 60 days of letrozole before screening
• 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 study 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

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (7)

City of Hope Corona

Corona, California, 92879, United States

Location

City of Hope Medical Center

Duarte, California, 91010, United States

Location

City of Hope Antelope Valley

Lancaster, California, 93534, United States

Location

City of Hope Mission Hills

Mission Hills, California, 91345, United States

Location

City of Hope South Pasadena

South Pasadena, California, 91030, United States

Location

City of Hope Upland

Upland, California, 91786, United States

Location

City of Hope West Covina

West Covina, California, 91790, United States

Location

Related Publications (2)

• Yuan Y, Lee JS, Yost SE, Frankel PH, Ruel C, Egelston CA, Guo W, Padam S, Tang A, Martinez N, Schmolze D, Presant C, Ebrahimi B, Yeon C, Sedrak M, Patel N, Portnow J, Lee P, Mortimer J. Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer. Eur J Cancer. 2021 Sep;154:11-20. doi: 10.1016/j.ejca.2021.05.035. Epub 2021 Jul 1.

  PMID: 34217908 DERIVED

• Egelston C, Guo W, Yost S, Lee JS, Rose D, Avalos C, Ye J, Frankel P, Schmolze D, Waisman J, Lee P, Yuan Y. Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer. J Immunother Cancer. 2021 Mar;9(3):e002084. doi: 10.1136/jitc-2020-002084.

  PMID: 33757987 DERIVED

Related Links

• Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer
• Pre-existing effector T-cell levels and augmented myeloid cell composition denote response to CDK4/6 inhibitor palbociclib and pembrolizumab in hormone receptor-positive metastatic breast cancer

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Fulvestrant; Letrozole; palbociclib; pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Paul Frankel, Ph.D.
• Organization: City of Hope

pfrankel@coh.org

6262185265

Study Officials

• Joanne Mortimer

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 18, 2016
• First Posted: May 20, 2016
• Study Start: September 30, 2016
• Primary Completion: October 31, 2025
• Study Completion: March 30, 2026
• Last Updated: February 24, 2026
• Results First Posted: February 24, 2026

Record last verified: 2026-02

Locations

US (7)