Clinical Trials /

Pembrolizumab and Tamoxifen With or Without Vorinostat for the Treatment of Estrogen Receptor Positive Breast Cancer

NCT04190056

Description:

This phase II trial studies how well pembrolizumab and tamoxifen with or without vorinostat work for the treatment of estrogen receptor positive breast cancer. 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. Hormone therapy with tamoxifen may may fight breast cancer by blocking the use of estrogen by the tumor cells. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial is being done to find a drug combination to better control estrogen receptor positive breast cancer and reduce the number of pills taken.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Tamoxifen With or Without Vorinostat for the Treatment of Estrogen Receptor Positive Breast Cancer
  • Official Title: Epigenetic Priming for Immune Therapy in ER-Positive Breast Cancer in Biomarker Select Population

Clinical Trial IDs

  • ORG STUDY ID: 197520
  • SECONDARY ID: NCI-2019-07572
  • NCT ID: NCT04190056

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Arm A (pembrolizumab, vorinostat, tamoxifen)
TamoxifenArm A (pembrolizumab, vorinostat, tamoxifen)
VorinostatL-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, ZolinzaArm A (pembrolizumab, vorinostat, tamoxifen)

Purpose

This phase II trial studies how well pembrolizumab and tamoxifen with or without vorinostat work for the treatment of estrogen receptor positive breast cancer. 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. Hormone therapy with tamoxifen may may fight breast cancer by blocking the use of estrogen by the tumor cells. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial is being done to find a drug combination to better control estrogen receptor positive breast cancer and reduce the number of pills taken.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To define the role of epigenetic immune priming in a biomarker enriched estrogen receptor
      (ER)+ breast cancer population on the basis of overall response rate.

      SECONDARY OBJECTIVES:

      I. To assess duration of response (DOR) 24-week landmark progression-free survival (PFS:24).

      II. Median PFS and overall survival (OS). III. Tumor responses will also be calculated by
      Immune Related Response-Criteria (irRC).

      EXPLORATORY OBJECTIVES:

      I. Evaluation of biomarker target threshold on response rate (retrospective cut off of 20%
      versus [vs] 10%).

      II. To assess the ratio of effector T cells: regulatory T cells in blood and tumor biopsies
      pre- and post-therapy.

      III. To evaluate inflammatory T cell signature changes in blood and tumor biopsies pre- and
      post-therapy.

      IV. To evaluate changes in number of myeloid-derived suppressor cells (MDSCs) in peripheral
      blood and tumor biopsies pre- and posttherapy.

      V. To evaluate changes in histone acetylation in peripheral blood cells and tumor biopsies
      pre- and post-therapy.

      VI. Initial comparison to vorinostat-induced PD-1 in lymphocytes, PD-L1 modulation.

      VII. Nanostring and 10 x sequencing and single cell immune phenotyping (on stored tissue for
      successful arms only).

      VIII. Impact of histone deacetylase (HDAC) inhibition of response to pembrolizumab vs.
      pembrolizumab in biomarker enriched population.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, vorinostat
      orally (PO) once daily (QD) for 4 days weekly, and tamoxifen PO QD on days 1-21. Cycles
      repeat every 21 days in the absence of disease progression of unacceptable toxicity.

      ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1 and tamoxifen PO QD on days
      1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable
      toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Arm A (pembrolizumab, vorinostat, tamoxifen)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1, vorinostat PO QD for 4 days weekly, and tamoxifen PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable toxicity.
  • Pembrolizumab
  • Tamoxifen
  • Vorinostat
Arm B (pembrolizumab, tamoxifen)ExperimentalPatients receive pembrolizumab IV over 30 minutes on day 1 and tamoxifen PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression of unacceptable toxicity.
  • Pembrolizumab
  • Tamoxifen

Eligibility Criteria

        Inclusion Criteria:

          -  Pre and postmenopausal women or men with stage IV ER+ breast cancer histological or
             cytological confirmation

          -  > 10% expression of PD-1/CTLA-4 dual staining in CD8 cells in tumor or blood

          -  Eastern Cooperative Oncology Group (ECOG) performance status of =< 1

          -  Understand and voluntarily sign an informed consent prior to any study-related
             assessments or procedures are conducted and are able to adhere to the study visit
             schedule and other protocol requirements

          -  Consent to paired tumor biopsy

          -  Measurable tumor by Response Evaluation Criteria in Solid Tumors (RECIST) criteria

          -  Per Good Clinical Practice, any toxicity related to prior therapies that, in the
             opinion of the investigator, would potentially be worsened with anti-PD1 therapy
             should be resolved to less than grade 1

          -  Absolute neutrophil count (ANC) >= 1.5 X 10^9/L

          -  Hemoglobin (Hgb) >= 9 g/dL (may transfuse if clinically indicated)

          -  Platelets (plt) >= 100 x 10^9/L

          -  Potassium within normal range, or correctable with supplements

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper
             limit normal (ULN) or =< 5.0 x ULN if liver tumor is present

          -  Serum total bilirubin =< 1.5 x ULN

          -  Serum creatinine =< 1.5 x ULN, or 24-hr clearance >= 60 ml/min

          -  Females of childbearing potential (defined as sexually mature women who):

               -  Has not undergone a hysterectomy (the surgical removal of the uterus) or
                  bilateral oophorectomy (the surgical removal of both ovaries) or,

               -  Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
                  has had menses at any time during the preceding 24 consecutive months) must have

                    -  Negative serum pregnancy test within 14 days before starting study treatment
                       in females of childbearing potential (FCBP) and willingness to adhere to
                       acceptable forms or birth control (a physician-approved contraceptive method
                       (oral, injectable, or implantable hormonal contraceptive; tubal ligation;
                       intra-uterine device; barrier contraceptive with spermicide; or vasectomized
                       partner)

          -  All female and male participants must agree to use approved contraception during the
             treatment period and for at least 18 weeks after the last dose of study treatment and
             refrain from donating sperm during this period

        Exclusion Criteria:

          -  Prior treatment with pembrolizumab or other PD-(L)1

          -  Any significant medical condition, laboratory abnormalities, which places the subject
             at unacceptable risk if he/she were to participate in the study

          -  Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis

          -  Has 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)

          -  Has a history of hepatitis B virus (HBV)

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the study, interfere with the subject's
             participation for the full duration of the study, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator

          -  Symptomatic central nervous system metastases. Subjects with brain metastases that
             have been previously treated and are stable for 6 weeks are allowed

          -  Persistent diarrhea or malabsorption >= National Cancer Institute (NCI) Common
             Terminology Criteria for Adverse Events (CTCAE) grade 2, despite medical management

          -  Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA)
             class 3 or 4 congestive heart failure

          -  Prior systemic cancer-directed treatments or investigational modalities =< 5
             half-lives or 4 weeks, whichever is shorter, prior to starting study drug or who have
             not recovered from side effects of such therapy (except alopecia)

          -  Active autoimmune disease except for vitiligo or hypothyroidism

          -  Active and ongoing steroid use, except for non-systemically absorbed treatments (such
             as inhaled or topical steroid therapy for asthma, chronic obstructive pulmonary
             disease (COPD), allergic rhinitis)

          -  Major surgery =< 2 weeks prior to starting a study drug or who have not recovered from
             side effects of such therapy

          -  Pregnant or breastfeeding

          -  Known human immunodeficiency virus (HIV) infection

          -  Known history of tuberculosis

          -  Known allergic reaction or intolerability to tamoxifen

          -  Patients with prior history of deep vein thrombosis (DVT)s must be on therapeutic or
             preventive anticoagulation
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 24 weeks
Safety Issue:
Description:Will be defined as the proportion of participants randomized to that arm whose status is stable disease (SD) or better (complete response (CR), partial response (PR)). The observed ORR will be compared to the respective null (ineffective) rate using the decision rule provided by the Simon's two-stage design. In addition to calculating the ORR, we will calculate the corresponding one-sided 95% confidence interval by appropriately accounting for the Simon's two-stage design.

Secondary Outcome Measures

Measure:Duration of response (DOR)
Time Frame:Up to 24 weeks
Safety Issue:
Description:The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that recurrent disease is objectively documented. Duration of stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started. Will use median DOR (computed by the Kaplan-Meier estimator) to summarize. The respective confidence intervals will be computed as well.
Measure:Median progression free survival (PFS)
Time Frame:Up to 48 months
Safety Issue:
Description:Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death from any cause on study, whichever occurs first. Will use median PFS (computed by the Kaplan-Meier estimator) to summarize. The respective confidence intervals will be computed as well.
Measure:Overall survival (OS)
Time Frame:Up to 48 months
Safety Issue:
Description:Will use median OS (computed by the Kaplan-Meier estimator) to summarize from initiation of study treatment to the time of death from any cause on study. The respective confidence intervals will be computed as well.
Measure:Percentage of participants with tumor responses
Time Frame:Up to 24 months
Safety Issue:
Description:Will use percentages (% Immune Related Response-Criteria (irRC)) through study completion to summarize. The respective confidence intervals will be computed as well.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

December 4, 2019