Reversing Therapy Resistance With Epigenetic-Immune Modification

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02395627
• Collaborator: Avon Foundation (Other), Merck Sharp & Dohme LLC (Industry)
• Enrollment: 38
• Location: 1
• Arms: 3
• Actual Duration (Months): 49.1
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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, tamoxifen, 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)

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Tamoxifen; Drug: Vorinostat; Drug: Pembrolizumab	Phase 2

Detailed Description

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 Histone deacetylase (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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Reversing Therapy Resistance With Epigenetic-immune Modification: Phase II Trial of Vorinostat, Tamoxifen and Pembrolizumab in Hormone Receptor Expressing Advanced Breast Cancer
• Actual Study Start Date: May 4, 2015
• Actual Primary Completion Date: Jun 8, 2019
• Actual Study Completion Date: Jun 8, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab Cycle 1 (Group A) 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)	Drug: Tamoxifen; Other Names: Nolvadex ; Drug: Vorinostat; Other Names: Zolinza ; Drug: Pembrolizumab; Other Names: Keytruda
Experimental: Pembrolizumab Cycle 2 (Group B) 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)	Drug: Tamoxifen; Other Names: Nolvadex ; Drug: Vorinostat; Other Names: Zolinza ; Drug: Pembrolizumab; Other Names: Keytruda
Experimental: Pembrolizumab Cycle 1 (Group C) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Drug: Vorinostat; Other Names: Zolinza ; Drug: Pembrolizumab; Other Names: Keytruda

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) [Up to 24 weeks]

   Objective response rate (ORR) will be defined as the proportion of participants whose status is stable disease (SD) or better (complete response (CR), partial response (PR)) at 24 weeks' follow-up as measured by Response Evaluation Criteria in Solid Tumors (RECIST). The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.

2. Number of Participants With Treatment-related Adverse Events (AE) [Up to 1 year post treatment, approximately 24 months]

   Each patient who received at least 1 dose of any of the study drugs will be assessed periodically for the development of any grade 3 and higher treatment-related toxicity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4. The investigators will also pay particular attention to pembrolizumab adverse events of clinical interest (ECI), which will predominantly be of immune origin.

Secondary Outcome Measures

1. Duration of Response [Up to 24 months]

   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).

2. Progression Free Survival [Up to 36 months]

   Progression-free survival (PFS) is defined as the length of time during and after the treatment that the participant has achieved an objective response, but does not progress as measured by RECIST v.1.1

3. Overall Survival (OS) [Up to 36 months]

   OS is defined as the length of time from the start of treatment for participants until death or the study has ended, whichever comes first.

4. Number of Participants With Tumor Responses Calculated by Immune Related Response-Criteria (irRC) [Up to 24 months]

   In the irRC, an immune-related Complete Response (irCR) is defined as the disappearance of all lesions, measured or unmeasured, and no new lesions; an immune-related Partial Response (irPR) is defined as a 50% drop in tumour burden from baseline, and immune-related Progressive Disease (irPD) is a 25% increase in tumour burden from the lowest level recorded. All other responses are considered immune-related Stable Disease (irSD). The number of participants with a tumor response of either irCR or irPR will be reported.

5. Number of Participants With a Clinical Response (Clinical Benefit) Based on PD-L1 Expression to Epigenetic Immune Priming [Up to 18 weeks, at Cycle 6]

   PD-L1 protein expression on tumor tissue from pre-treatment and post-Cycle-3 biopsies, and any other tumor biospecimens obtained, were evaluated immunohistochemically. Patients were categorized based on detectable PD-L1 expression as Positive or Negative for expression. Participants with positive PD-L1 expression were then reviewed to determine if a clinical benefit was obtained at cycle 6. Clinical benefit was defined as a complete response or partial response per RECIST 1.1.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

• human epidermal growth factor receptor 2 (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;

• 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 ≥ 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/atopy 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, 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 breast feeding.

• Known Human Immunodeficiency Virus (HIV) infection and/or Hepatitis B or C positive.

• Known hypersensitivity to pembrolizumab or any of its excipients.

• 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 of CYP450 enzyme(s) are ineligible.

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco Medical Center	San Francisco	California	United States	94115

Sponsors and Collaborators

• University of California, San Francisco
• Avon Foundation
• Merck Sharp & Dohme LLC

Investigators

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

Study Documents (Full-Text)

• Informed Consent Form - Feb 27, 2018
• Study Protocol and Statistical Analysis Plan - Jul 28, 2016

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT02395627
• Other Study ID Numbers: 147523; NCI-2015-00815
• First Posted: Mar 23, 2015
• Last Update Posted: Jul 7, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by University of California, San Francisco: Hormone Therapy Resistant; Estrogen Receptor-Positive; Estrogen Receptor-Negative
• Additional relevant MeSH terms: Breast Neoplasms; Tamoxifen; Pembrolizumab; Vorinostat

Study Results

Participant Flow

Arm/Group Title	Pembrolizumab Cycle 1 (Group A)	Pembrolizumab Cycle 2 (Group B)	Pembrolizumab Cycle 1 (Group C)
Arm/Group 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) Tamoxifen Vorinostat Pembrolizumab	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) Tamoxifen Vorinostat Pembrolizumab	Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1) Vorinostat Pembrolizumab
Period Title: Overall Study
STARTED	18	16	4
COMPLETED	15	13	4
NOT COMPLETED	3	3	0

Baseline Characteristics

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab Group B	Pembrolizumab Group C	Total
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Total of all reporting groups
Overall Participants	18	16	4	38
Age, Customized (Count of Participants)
30-39 years old	2 11.1%	4 25%	0 0%	6 15.8%
40-49 years old	4 22.2%	3 18.8%	1 25%	8 21.1%
50-59 years old	5 27.8%	3 18.8%	2 50%	10 26.3%
60-69 years old	4 22.2%	5 31.3%	1 25%	10 26.3%
70-79 years old	2 11.1%	1 6.3%	0 0%	3 7.9%
80-89 years old	1 5.6%	0 0%	0 0%	1 2.6%
Sex: Female, Male (Count of Participants)
Female	18 100%	15 93.8%	4 100%	37 97.4%
Male	0 0%	1 6.3%	0 0%	1 2.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.6%	0 0%	1 25%	2 5.3%
Not Hispanic or Latino	14 77.8%	13 81.3%	2 50%	29 76.3%
Unknown or Not Reported	3 16.7%	3 18.8%	1 25%	7 18.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 5.6%	2 12.5%	0 0%	3 7.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 5.6%	3 18.8%	0 0%	4 10.5%
White	12 66.7%	8 50%	3 75%	23 60.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	4 22.2%	3 18.8%	1 25%	8 21.1%
Region of Enrollment (participants) [Number]
United States	18 100%	16 100%	4 100%	38 100%
Estrogen Receptor (ER) Type (Count of Participants)
ER Positive (ER+)	18 100%	16 100%	0 0%	34 89.5%
ER Negative (ER-)	0 0%	0 0%	4 100%	4 10.5%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR)
Description	Objective response rate (ORR) will be defined as the proportion of participants whose status is stable disease (SD) or better (complete response (CR), partial response (PR)) at 24 weeks' follow-up as measured by Response Evaluation Criteria in Solid Tumors (RECIST). The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
Time Frame	Up to 24 weeks

Outcome Measure Data

Analysis Population Description

Participants in Group C were off treatment prior to assessment and not included in this analysis

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab: Group B	Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Measure Participants	15	13	0
Number [percentage of participants]	6.67 37.1%	0 0%

2. Primary Outcome

Title	Number of Participants With Treatment-related Adverse Events (AE)
Description	Each patient who received at least 1 dose of any of the study drugs will be assessed periodically for the development of any grade 3 and higher treatment-related toxicity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4. The investigators will also pay particular attention to pembrolizumab adverse events of clinical interest (ECI), which will predominantly be of immune origin.
Time Frame	Up to 1 year post treatment, approximately 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab Group B	Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Measure Participants	18	16	4
Anorexia	0 0%	1 6.3%	0 0%
Fatigue	1 5.6%	1 6.3%	0 0%
Thrombocytopenia	1 5.6%	1 6.3%	1 25%
Elevated Transaminitis (Liver Enzymes)	2 11.1%	0 0%	0 0%
Hyponatremia	1 5.6%	1 6.3%	0 0%
Stroke	1 5.6%	0 0%	0 0%

3. Secondary Outcome

Title	Duration of Response
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).
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

No participants from Group C achieved an objective response

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab Group B	Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Measure Participants	15	13	0
Median (Full Range) [months]	17.0	8.8

4. Secondary Outcome

Title	Progression Free Survival
Description	Progression-free survival (PFS) is defined as the length of time during and after the treatment that the participant has achieved an objective response, but does not progress as measured by RECIST v.1.1
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

No participants from Group C achieved an objective response

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab Group B	Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Measure Participants	15	13	0
Median (Full Range) [months]	2.57	2.63

5. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the length of time from the start of treatment for participants until death or the study has ended, whichever comes first.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab Group B	Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Measure Participants	15	13	4
Median (Full Range) [months]	14.3	15.0	7.8

6. Secondary Outcome

Title	Number of Participants With Tumor Responses Calculated by Immune Related Response-Criteria (irRC)
Description	In the irRC, an immune-related Complete Response (irCR) is defined as the disappearance of all lesions, measured or unmeasured, and no new lesions; an immune-related Partial Response (irPR) is defined as a 50% drop in tumour burden from baseline, and immune-related Progressive Disease (irPD) is a 25% increase in tumour burden from the lowest level recorded. All other responses are considered immune-related Stable Disease (irSD). The number of participants with a tumor response of either irCR or irPR will be reported.
Time Frame	Up to 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab Group B	Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Measure Participants	15	13	4
Count of Participants [Participants]	1 5.6%	0 0%	0 0%

7. Secondary Outcome

Title	Number of Participants With a Clinical Response (Clinical Benefit) Based on PD-L1 Expression to Epigenetic Immune Priming
Description	PD-L1 protein expression on tumor tissue from pre-treatment and post-Cycle-3 biopsies, and any other tumor biospecimens obtained, were evaluated immunohistochemically. Patients were categorized based on detectable PD-L1 expression as Positive or Negative for expression. Participants with positive PD-L1 expression were then reviewed to determine if a clinical benefit was obtained at cycle 6. Clinical benefit was defined as a complete response or partial response per RECIST 1.1.
Time Frame	Up to 18 weeks, at Cycle 6

Outcome Measure Data

Analysis Population Description

All necessary data required for inclusion in this analysis could not be obtained for participants in Group C

Arm/Group Title	Pembrolizumab Group A	Pembrolizumab Group B	Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)	Estrogen Receptor Positive (ER+) participants Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)	Estrogen Receptor Negative (ER-) participants Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
Measure Participants	15	13	0
PD-L1 Negative	14 77.8%	12 75%
PD-L1 Positive	1 5.6%	1 6.3%
PD-L1 Positive with clinical benefit at cycle 6	0 0%	0 0%

Adverse Events

Time Frame	Up to 24 months
Arm/Group Title	Pembrolizumab Group A		Pembrolizumab Group B		Pembrolizumab Group C
Arm/Group Description	Estrogen Receptor Positive participants (ER+) Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group A: Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)		Estrogen Receptor Positive participants (ER+) Tamoxifen: 20 mg daily orally (starting at Cycle 1) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Group B: Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 2)		Estrogen Receptor Negative participants (ER-) Vorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
All Cause Mortality
	Pembrolizumab Group A		Pembrolizumab Group B		Pembrolizumab Group C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		0/16 (0%)		0/4 (0%)
Serious Adverse Events
	Pembrolizumab Group A		Pembrolizumab Group B		Pembrolizumab Group C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/18 (33.3%)		4/16 (25%)		0/4 (0%)
Blood and lymphatic system disorders
Thrombocytopenia	0/18 (0%)	0	1/16 (6.3%)	1	0/4 (0%)	0
Gastrointestinal disorders
Abdominal Pain	0/18 (0%)	0	1/16 (6.3%)	1	0/4 (0%)	0
Infections and infestations
Sepsis	0/18 (0%)	0	1/16 (6.3%)	1	0/4 (0%)	0
Investigations
Aspartate aminotransferase increased	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Weight Loss	0/18 (0%)	0	1/16 (6.3%)	1	0/4 (0%)	0
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Musculoskeletal and connective tissue disorder - Other	0/18 (0%)	0	1/16 (6.3%)	1	0/4 (0%)	0
Nervous system disorders
Dysarthria	1/18 (5.6%)	2	0/16 (0%)	0	0/4 (0%)	0
Intracranial hemorrhage	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Renal and urinary disorders
Acute renal failure (ARF)	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Vascular disorders
Hematoma	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Other (Not Including Serious) Adverse Events
	Pembrolizumab Group A		Pembrolizumab Group B		Pembrolizumab Group C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/18 (94.4%)		15/16 (93.8%)		4/4 (100%)
Endocrine disorders
Hypothyroidism	2/18 (11.1%)	3	0/16 (0%)	0	0/4 (0%)	0
Gastrointestinal disorders
Diarrhea	6/18 (33.3%)	16	4/16 (25%)	4	2/4 (50%)	2
Nausea	6/18 (33.3%)	8	4/16 (25%)	10	2/4 (50%)	2
Vomiting	6/18 (33.3%)	6	3/16 (18.8%)	4	0/4 (0%)	0
Constipation	6/18 (33.3%)	6	4/16 (25%)	5	2/4 (50%)	2
Dry mouth	4/18 (22.2%)	4	2/16 (12.5%)	2	0/4 (0%)	0
Abdominal pain	4/18 (22.2%)	4	2/16 (12.5%)	2	0/4 (0%)	0
Flatulence	2/18 (11.1%)	2	0/16 (0%)	0	0/4 (0%)	0
Gastritis	1/18 (5.6%)	2	1/16 (6.3%)	1	0/4 (0%)	0
Dysphagia	1/18 (5.6%)	1	3/16 (18.8%)	3	0/4 (0%)	0
Stomach Pain	0/18 (0%)	0	0/16 (0%)	0	1/4 (25%)	1
Colitis	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
General disorders
Fatigue	11/18 (61.1%)	20	5/16 (31.3%)	7	4/4 (100%)	8
Pain	4/18 (22.2%)	6	2/16 (12.5%)	2	0/4 (0%)	0
Non-cardiac chest pain	2/18 (11.1%)	2	0/16 (0%)	0	2/4 (50%)	2
Edema limbs	2/18 (11.1%)	2	1/16 (6.3%)	1	0/4 (0%)	0
Fever	2/18 (11.1%)	2	1/16 (6.3%)	1	0/4 (0%)	0
Investigations
Platelet count decreased	4/18 (22.2%)	7	3/16 (18.8%)	9	1/4 (25%)	4
Weight loss	3/18 (16.7%)	4	4/16 (25%)	6	2/4 (50%)	3
Creatinine increased	2/18 (11.1%)	2	4/16 (25%)	8	0/4 (0%)	0
Hypokalemia	3/18 (16.7%)	4	2/16 (12.5%)	2	0/4 (0%)	0
Hyponatremia	1/18 (5.6%)	2	1/16 (6.3%)	2	0/4 (0%)	0
Hypophosphatemia	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Neutropenia	1/18 (5.6%)	1	1/16 (6.3%)	1	0/4 (0%)	0
Alkaline phosphatase increased	2/18 (11.1%)	2	0/16 (0%)	0	0/4 (0%)	0
Aspartate aminotransferase increased	1/18 (5.6%)	2	1/16 (6.3%)	2	0/4 (0%)	0
Metabolism and nutrition disorders
Anorexia	5/18 (27.8%)	10	6/16 (37.5%)	6	4/4 (100%)	5
Musculoskeletal and connective tissue disorders
Back Pain	4/18 (22.2%)	4	1/16 (6.3%)	1	0/4 (0%)	0
Arthralgia	1/18 (5.6%)	1	1/16 (6.3%)	1	0/4 (0%)	0
Nervous system disorders
Dysgeusia	4/18 (22.2%)	8	2/16 (12.5%)	4	0/4 (0%)	0
Headache	4/18 (22.2%)	4	1/16 (6.3%)	3	0/4 (0%)	0
Stroke	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Psychiatric disorders
Anxiety	1/18 (5.6%)	1	1/16 (6.3%)	1	0/4 (0%)	0
Reproductive system and breast disorders
Breast Pain	3/18 (16.7%)	3	0/16 (0%)	0	0/4 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/18 (11.1%)	2	3/16 (18.8%)	3	2/4 (50%)	2
Cough	3/18 (16.7%)	3	1/16 (6.3%)	1	2/4 (50%)	3
Pneumonitis	1/18 (5.6%)	1	0/16 (0%)	0	0/4 (0%)	0
Skin and subcutaneous tissue disorders
Rash maculo-papular	2/18 (11.1%)	3	0/16 (0%)	0	0/4 (0%)	0
Vascular disorders
Hot Flashes	4/18 (22.2%)	4	2/16 (12.5%)	2	1/4 (25%)	1

Limitations/Caveats

Study was closed early due to insufficient efficacy in an unselected patient population and slow accrual which resulted in small sample sizes by arm. Approximately 29 participants were needed, per arm, for sufficiently powered statistical analysis.

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.