Expired Study
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San Francisco, California 94115


The investigators propose a randomized two arm trial, using Simon's 2-stage design, in ER+ patients with therapy resistant breast cancer to test the optimal sequence and dosing of epigenetic immune priming in hormone therapy resistance breast cancer. A third arm (Arm C) will include ER-negative patients who will follow the concurrent priming, but exclude tamoxifen. The two arms all include vorinostat, TAM and pembrolizumab to evaluate - Sequential priming - begin pembrolizumab in Cycle 1 (Arm B and Arm C) and, - Concurrent priming with maximal dosing of both epigenetic and immune modulators- begin pembrolizumab on day 1 in Cycle 2 (Arm A)

Study summary:

Unique aspects of this study: This is the first study to look at the response of hormone therapy resistance breast cancer to epigenetic immune priming. It is also the first study to look at the combination of an HDAC inhibitor (vorinostat), an anti-estrogen (tamoxifen) and a PD-1 inhibitor, pembrolizumab in pre or postmenopausal patients with ER+ advanced breast cancer with progression on multiple prior therapies. Recent preclinical studies have further suggested that epigenetic priming may be even more effective in ER-negative tumors that do not respond to immune check point inhibitors or have low PD-1/PD-L1 expression. The goal of this study is to demonstrate that Vorinostat can increase PD-1 and PD-L1 expression. In a third arm the study will evaluate the role of epigenetic priming in tumors that are ER-negative.


NOTE: Study no longer enrolling ER+ patients as of 12/29/2016. Now enrolling ER- patients. Inclusion Criteria: - Pre and postmenopausal women or men with stage IV ER+ breast cancer histological or cytological confirmation ER-positive tumors - Progressed after at least one line of hormonal therapy - Any number of prior chemotherapy in the metastatic setting - Any number of prior hormonal therapies. - HER2 positive or negative ER-Negative tumors - PD-L1 low, high or unknown - Progression after prior PD-1 or PD-L1 inhibitors allowed - HER2 positive or negative - 18 years or older - Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. - Understand and voluntarily sign an informed consent prior to any study-related assessments or procedures are conducted and are able adhere to the study visit schedule and other protocol requirements. - Consent to paired tumor biopsy, for accessible tumors - Measureable tumor by RECIST criteria v.1.1 - Archived tumor tissue (minimum of 8 slides for paraffin-embedded tumor tissue) for assessment of tumor-based biomarkers and immune score is required for eligibility. - 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 - Adequate organ function within 14 days of study start: - Absolute neutrophil count (ANC) ≥ 1.5 X 109/L - Hemoglobin (Hgb) ≥9g/dL (may transfuse if clinically indicated) - Platelets (plt) ≥ 100 x 109/L - Potassium within normal range, or correctable with supplements; - AST and 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 ≥ 60ml/min; and - Females of child-bearing potential (defined as a 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 7 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). - Male subjects with female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study Exclusion Criteria: - Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. - Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. - Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. - Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. - Patients may continue on ovarian suppression - Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. - Any condition that confounds the ability to interpret data from the study. - 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 ≥ NCI 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). - Has an active auto-immune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopia would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. - Has evidence of interstitial lung disease or active, non-infectious pneumonitis. - Has an active infection requiring systemic therapy. - Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. - Is pregnant or breastfeeding, or expecting to conceive or father 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. - Active and ongoing steroid use, except for non-systemically absorbed treatments (such as inhaled or topical steroid therapy for asthma, 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 breast feeding. - Known Human Immunodeficiency Virus (HIV) infection and/or Hepatitis B or C positive. - Known hypersensitivity to pembrolizumab or any of its insipients. - Has received a live vaccine within 30 days prior to the first dose of trial treatment. - Patients receiving medications or substances that are strong inhibitors or inducers ofCYP450 enzyme(s) are ineligible. Lists including medications and substances known or with the potential to interact with the specified CYP450 enzyme(s) isoenzymes are provided in Appendix 5. - Pregnant women are excluded from this study because vorinostat, tamoxifen and PD-1 are drug classes with 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, breastfeeding should be discontinued if the mother is treated with vorinostat, tamoxifen and PD-1 inhibitors.

Study is Available At:

Original ID:




Secondary ID:


Study Acronym:

Brief Title:

Reversing Therapy Resistance With Epigenetic-Immune Modification

Official Title:

Reversing Therapy Resistance With Epigenetic-immune Modification: Phase II Trial of Vorinostat, Tamoxifen and Pembrolizumab in Hormone Receptor Expressing Advanced Breast Cancer

Overall Status:

Active, not recruiting

Study Phase:

Phase 2



Minimum Age:

18 Years

Maximum Age:


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

University of California, San Francisco

Oversight Authority:

United States: Food and Drug Administration

Reasons Why Stopped:

Study Type:


Study Design:

Number of Arms:


Number of Groups:


Total Enrollment:


Enrollment Type:


Overall Contact Information

Official Name:Pamela Munster, MD
Principal Investigator
University of California, San Francisco

Study Dates

Start Date:March 2015
Completion Date:December 20, 2021
Completion Type:Anticipated
Primary Completion Date:December 20, 2019
Primary Completion Type:Anticipated
Verification Date:January 2019
Last Changed Date:January 17, 2019
First Received Date:March 17, 2015

Study Outcomes

Outcome Type:Secondary Outcome
Measure:Response of PD-L1 expression to epigenetic immune priming
Time Frame:Up to 9 weeks (end of course 3)
Safety Issues:False
Description:As measured by AE evaluation in combination with RECIST v.1.1
Outcome Type:Secondary Outcome
Measure:Tumor Responses
Time Frame:Up to 1 year
Safety Issues:False
Description:As calculated by Immune Related Response-Criteria (irRC)
Outcome Type:Secondary Outcome
Measure:Overall Survival
Time Frame:Up to 1 year
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Median Progression Free Survival
Time Frame:From start of treatment to time of progression, assessed up to 1 year
Safety Issues:False
Description:As measured by RECIST v1.1
Outcome Type:Secondary Outcome
Measure:Progression Free Survival
Time Frame:From start of treatment to time of progression, assessed at 24 weeks
Safety Issues:False
Description:As measured by RECIST v.1.1
Outcome Type:Primary Outcome
Measure:Adverse Events
Time Frame:Up to 90 days
Safety Issues:False
Description:graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Outcome Type:Primary Outcome
Measure:Overall Response Rate
Time Frame:Week 24
Safety Issues:False
Description:Defined as Complete Response + Partial Response + Stable Disease

Study Interventions

Intervention Type:Drug
Arm Name:Pembrolizumab Cycle 1 (Group A)
Intervention Type:Drug
Arm Name:Pembrolizumab Cycle 1 (Group A)
Intervention Type:Drug
Arm Name:Pembrolizumab Cycle 1 (Group A)

Study Arms

Study Arm Type:Experimental
Arm Name:Pembrolizumab Cycle 1 (Group A)
Description:Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Study Arm Type:Experimental
Arm Name:Pembrolizumab Cycle 2 (Group B)
Description:Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)
Study Arm Type:Experimental
Arm Name:Pembrolizumab Cycle 1 (Group C)
Description:Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Pamela Munster

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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