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Reversing Therapy Resistance With Epigenetic-Immune Modification

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ClinicalTrials.gov Identifier: NCT02395627
Recruitment Status : Active, not recruiting
First Posted : March 23, 2015
Last Update Posted : January 21, 2019
Sponsor:
Information provided by (Responsible Party):
Pamela Munster, University of California, San Francisco

Tracking Information
First Submitted Date  ICMJE March 17, 2015
First Posted Date  ICMJE March 23, 2015
Last Update Posted Date January 21, 2019
Study Start Date  ICMJE March 2015
Estimated Primary Completion Date December 20, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 6, 2018)
  • Overall Response Rate [ Time Frame: Week 24 ]
    Defined as Complete Response + Partial Response + Stable Disease
  • Adverse Events [ Time Frame: Up to 90 days ]
    graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Original Primary Outcome Measures  ICMJE
 (submitted: March 20, 2015)
  • Overall Response Rate [ Time Frame: Week 24 ]
    Defined as Complete Response + Partial Response + Stable Disease
  • Adverse Events [ Time Frame: Up to 2 years ]
Change History Complete list of historical versions of study NCT02395627 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2018)
  • Progression Free Survival [ Time Frame: From start of treatment to time of progression, assessed at 24 weeks ]
    As measured by RECIST v.1.1
  • Median Progression Free Survival [ Time Frame: From start of treatment to time of progression, assessed up to 1 year ]
    As measured by RECIST v1.1
  • Overall Survival [ Time Frame: Up to 1 year ]
  • Tumor Responses [ Time Frame: Up to 1 year ]
    As calculated by Immune Related Response-Criteria (irRC)
  • Response of PD-L1 expression to epigenetic immune priming [ Time Frame: Up to 9 weeks (end of course 3) ]
    As measured by AE evaluation in combination with RECIST v.1.1
Original Secondary Outcome Measures  ICMJE
 (submitted: March 20, 2015)
  • Progression Free Survival [ Time Frame: Week 24 ]
    As measured by RECIST v.1.1
  • Median Progression Free Survival [ Time Frame: Week 24 ]
    As measured by RECIST v1.1
  • Overall Survival [ Time Frame: Up to 2 years ]
  • Tumor Responses [ Time Frame: Up to 2 years ]
    As calculated by Immune Related Response-Criteria (irRC)
  • Response to epigenetic immune priming [ Time Frame: Up to 2 years ]
    As measured by AE evaluation in combination with RECIST v.1.1
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Reversing Therapy Resistance With Epigenetic-Immune Modification
Official Title  ICMJE Reversing Therapy Resistance With Epigenetic-immune Modification: Phase II Trial of Vorinostat, Tamoxifen and Pembrolizumab in Hormone Receptor Expressing Advanced Breast Cancer
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, 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Neoplasms
Intervention  ICMJE
  • Drug: Tamoxifen
  • Drug: Vorinostat
  • Drug: pembrolizumab
Study Arms  ICMJE
  • 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)
    Interventions:
    • Drug: Tamoxifen
    • Drug: Vorinostat
    • Drug: pembrolizumab
  • 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)
    Interventions:
    • Drug: Tamoxifen
    • Drug: Vorinostat
    • Drug: pembrolizumab
  • 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)
    Interventions:
    • Drug: Vorinostat
    • Drug: pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 17, 2019)
38
Original Estimated Enrollment  ICMJE
 (submitted: March 20, 2015)
58
Estimated Study Completion Date  ICMJE December 20, 2021
Estimated Primary Completion Date December 20, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02395627
Other Study ID Numbers  ICMJE 147523
NCI-2015-00815 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Pamela Munster, University of California, San Francisco
Study Sponsor  ICMJE Pamela Munster
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Pamela Munster, MD University of California, San Francisco
PRS Account University of California, San Francisco
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP