Reversing Therapy Resistance With Epigenetic-Immune Modification

NCT02395627 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: 147523NCI-2015-00815
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

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)

Conditions

Breast Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (5)

• Duration of Response

  Up to 24 months

• Progression Free Survival

  Up to 36 months

• Overall Survival (OS)

  Up to 36 months

• Number of Participants With Tumor Responses Calculated by Immune Related Response-Criteria (irRC)

  Up to 24 months

• 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

Study Arms (3)

Pembrolizumab Cycle 1 (Group A)

EXPERIMENTAL

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; Drug: Vorinostat; Drug: Pembrolizumab

Pembrolizumab Cycle 2 (Group B)

EXPERIMENTAL

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; Drug: Vorinostat; Drug: Pembrolizumab

Pembrolizumab Cycle 1 (Group C)

EXPERIMENTAL

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; Drug: Pembrolizumab

Interventions

Tamoxifen DRUG

Also known as: Nolvadex

Pembrolizumab Cycle 1 (Group A); Pembrolizumab Cycle 2 (Group B)

Vorinostat DRUG

Also known as: Zolinza

Pembrolizumab Cycle 1 (Group A); Pembrolizumab Cycle 1 (Group C); Pembrolizumab Cycle 2 (Group B)

Pembrolizumab DRUG

Also known as: Keytruda

Pembrolizumab Cycle 1 (Group A); Pembrolizumab Cycle 1 (Group C); Pembrolizumab Cycle 2 (Group B)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (1)

University of California, San Francisco Medical Center

San Francisco, California, 94115, United States

Location

Related Publications (1)

• 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.

  PMID: 32681091 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Tamoxifen; Vorinostat; pembrolizumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Limitations and 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.

Results Point of Contact

• Title: Dr. Pamela Munster, MD
• Organization: University of California, San Francisco

Pamela.Munster@ucsf.edu

(415) 502-3598

Study Officials

• Pamela Munster, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 17, 2015
• First Posted: March 23, 2015
• Study Start: May 4, 2015
• Primary Completion: June 8, 2019
• Study Completion: June 8, 2019
• Last Updated: July 7, 2020
• Results First Posted: July 7, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)