Reversing Therapy Resistance With Epigenetic-Immune Modification

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

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)

Study Overview

• Status: Terminated
• Conditions: Breast Neoplasms
• Intervention / Treatment: Drug: Tamoxifen; Drug: Pembrolizumab; Drug: Vorinostat

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 Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • University of California, San Francisco Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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: Pembrolizumab; Other Names: Keytruda; Drug: Vorinostat; Other Names: Zolinza
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: Pembrolizumab; Other Names: Keytruda; Drug: Vorinostat; Other Names: Zolinza
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: Pembrolizumab; Other Names: Keytruda; Drug: Vorinostat; Other Names: Zolinza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	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.	Up to 24 weeks
Number of Participants With Treatment-related Adverse Events (AE)	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.	Up to 1 year post treatment, approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response	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).	Up to 24 months
Progression Free Survival	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	Up to 36 months
Overall Survival (OS)	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.	Up to 36 months
Number of Participants With Tumor Responses Calculated by Immune Related Response-Criteria (irRC)	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.	Up to 24 months
Number of Participants With a Clinical Response (Clinical Benefit) Based on PD-L1 Expression to Epigenetic Immune Priming	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.	Up to 18 weeks, at Cycle 6

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Merck Sharp & Dohme LLC; Avon Foundation
• Investigators: Principal Investigator: Pamela Munster, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Terranova-Barberio M, Pawlowska N, Dhawan M, Moasser M, Chien AJ, Melisko ME, Rugo H, Rahimi R, Deal T, Daud A, Rosenblum MD, Thomas S, Munster PN. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020 Jul 17;11(1):3584. doi: 10.1038/s41467-020-17414-y.

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2015
• Primary Completion (Actual): June 8, 2019
• Study Completion (Actual): June 8, 2019

Study Registration Dates

• First Submitted: March 17, 2015
• First Submitted That Met QC Criteria: March 20, 2015
• First Posted (Estimate): March 23, 2015

Study Record Updates

• Last Update Posted (Actual): July 7, 2020
• Last Update Submitted That Met QC Criteria: June 22, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Hormone Therapy Resistant; Estrogen Receptor-Positive; Estrogen Receptor-Negative
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Immunological; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Histone Deacetylase Inhibitors; Pembrolizumab; Tamoxifen; Vorinostat
• Other Study ID Numbers: 147523; NCI-2015-00815 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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