Clinical Trials /

Reversing Therapy Resistance With Epigenetic-Immune Modification

NCT02395627

Description:

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)

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 147523
  • NCT ID: NCT02395627

Conditions

  • Breast Neoplasms

Interventions

DrugSynonymsArms
TamoxifenPembrolizumab Cycle 1 (Group A)
VorinostatPembrolizumab Cycle 1 (Group A)
pembrolizumabPembrolizumab Cycle 1 (Group A)

Purpose

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)

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
      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.
    

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab Cycle 1 (Group A)ExperimentalTamoxifen: 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
Pembrolizumab Cycle 2 (Group B)ExperimentalTamoxifen: 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
Pembrolizumab Cycle 1 (Group C)ExperimentalVorinostat: 400 mg 5 days every 7 orally (starting at Cycle 1) Pembrolizumab: 200 mg every 3 weeks intravenously (starting at Cycle 1)
  • Vorinostat
  • pembrolizumab

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate
Time Frame:Week 24
Safety Issue:
Description:Defined as Complete Response + Partial Response + Stable Disease

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:Week 24
Safety Issue:
Description:As measured by RECIST v.1.1
Measure:Median Progression Free Survival
Time Frame:Week 24
Safety Issue:
Description:As measured by RECIST v1.1
Measure:Overall Survival
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Tumor Responses
Time Frame:Up to 2 years
Safety Issue:
Description:As calculated by Immune Related Response-Criteria (irRC)
Measure:Response to epigenetic immune priming
Time Frame:Up to 2 years
Safety Issue:
Description:As measured by AE evaluation in combination with RECIST v.1.1

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pamela Munster

Trial Keywords

  • Hormone Therapy Resistant
  • Estrogen Receptor-Positive
  • Estrogen Receptor-Negative

Last Updated

February 14, 2017