Clinical Trials /

Nivolumab, Ipilimumab, and Bicalutamide in Human Epidermal Growth Factor (HER) 2 Negative Breast Cancer Patients

NCT03650894

Description:

The goal of this protocol is to evaluate the safety and efficacy of an alternative systemic combination approach that omits or delays the use of chemotherapy in metastatic disease, while improving efficacy and durability of response. The approach combines two potentially effective and previously studied strategies: androgen receptor blockade and immune checkpoint therapy.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab, Ipilimumab, and Bicalutamide in Human Epidermal Growth Factor (HER) 2 Negative Breast Cancer Patients
  • Official Title: A Phase II Study of Nivolumab Combined With Bicalutamide and Ipilimumab in Metastatic HER2-negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: CA209-8H3
  • NCT ID: NCT03650894

Conditions

  • Breast Neoplasm Female
  • Breast Cancer
  • Breast Carcinoma
  • Breast Tumor

Interventions

DrugSynonymsArms
NivolumabOpdivoNivolumab, Ipilimumab, and bicalutamide
IpilimumabYervoyNivolumab, Ipilimumab, and bicalutamide
BicalutamideNivolumab, Ipilimumab, and bicalutamide

Purpose

The goal of this protocol is to evaluate the safety and efficacy of an alternative systemic combination approach that omits or delays the use of chemotherapy in metastatic disease, while improving efficacy and durability of response. The approach combines two potentially effective and previously studied strategies: androgen receptor blockade and immune checkpoint therapy.

Detailed Description

      This is a phase II trial to assess the clinical efficacy and safety of nivolumab
      (anti-Programmed Death receptor-1, or anti-PD-1) combined with bicalutamide (Androgen
      Receptor (AR) inhibitor) and ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4, or
      anit-CTLA4) in patients with advanced breast cancer.

      This study will include adult women with metastatic or locally advanced unresectable Human
      Epidermal Growth Factor (HER2)-negative breast cancer (by National Comprehensive Cancer
      Network (NCCN) criteria). Triple-negative breast cancer tumors will require confirmation of
      AR positivity at screening. Participants will have had no more than one line of previous
      chemotherapy in non-curative setting; subjects with metastatic progression within 1 year
      following completion of curative-intent chemotherapy are eligible if they have not received
      any additional lines of systemic therapy in the non-curative setting.

      Women who meet all of the study inclusion criteria, none of the study exclusion criteria, and
      agree to participate will receive a combination of the following:

        -  Intravenous nivolumab 240mg, every 2 weeks until progression or unacceptable toxicity

        -  Intravenous ipilimumab 1mg/kg, every 6 weeks until progression or unacceptable toxicity

        -  Oral bicalutamide 150mg, daily until progression or unacceptable toxicity

      Participants are to be treated for up to 24 months. Patients who have ongoing response will
      discontinue ipilimumab and nivolumab after 24 months, but at the discretion of the
      investigator may continue bicalutamide, and will continue assessments as per standard of
      care. Any patient who subsequently progresses will have the option to resume treatment upon
      disease progression.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab, Ipilimumab, and bicalutamideExperimentalParticipants will receive nivolumab plus ipilimumab combination therapy. Participants should receive nivolumab at a dose of 240 milligrams (mg) fixed dose as a 30-minute intravenous (IV) infusion prepared in 50 milliliter (ml) normal saline (NS) every 2 weeks until progression. Participants should receive ipilimumab at a dose of 1 mg/kilogram as a 30-minute IV infusion prepared in 50 ml NS every 6 weeks. All subjects will take bicalutamide 150mg (3 x 50mg tablets) daily.
  • Nivolumab
  • Ipilimumab
  • Bicalutamide

Eligibility Criteria

        Inclusion Criteria:

          -  ECOG performance status of 0-1;

          -  Metastatic or locally advanced unresectable HER2-negative breast cancer (by NCCN
             criteria);

          -  Triple Negative Breast Cancer tumors will require confirmation of androgen-receptor
             (AR) positivity at screening (refer to laboratory manual for guidelines). Local
             testing permitted for eligibility if reviewed by a designated study pathologist;

          -  RECIST1.1 measurable disease;

          -  Participants must be willing (if clinically feasible) to provide a fresh tumor biopsy
             (or archived tissue). For archived tissue, a tissue block from the most recent biopsy
             is acceptable if no intervening anti-neoplastic therapies have been administered since
             the time of biopsy.

          -  Previous systemic chemotherapy: no greater than one line of previous chemotherapy in
             non-curative setting; subjects with metastatic progression within 1 year following
             completion of curative-intent chemotherapy are eligible if they have not received any
             additional lines of systemic therapy in the non-curative setting.

          -  Participants must have signed and dated an IRB/IEC approved written informed consent
             form in accordance with regulatory and institutional guidelines. This must be obtained
             before the performance of any protocol related procedures that are not part of normal
             patient care.

          -  Participants must be willing and able to comply with scheduled visits, treatment
             schedule, laboratory tests, tumor biopsies, and other requirements of the study

          -  Adequate hematologic and liver function (using CTCAE v4). (All baseline laboratory
             requirements will be assessed and should be obtained within 14 days prior to
             enrollment): WBC≥2000/μL; Neutrophils≥1500/μL; Platelets≥100 × 103/μL; Hemoglobin ≥9.0
             g/dL; AST≤3 × ULN; ALT ≤3 × ULN; Total bilirubin ≤1.5 × ULN (except in participants
             with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL). Subjects with
             elevations in LFTs related to underlying hepatic cancer involvement may be considered
             for enrollment (after discussion with lead PI) if ALT/AST is ≤5 x ULN and Total
             bilirubin ≤3 × ULN.

          -  Female and Age ≥18 years. (Men are excluded because of potential confounding effects
             of sex on correlative analyses)

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to
             the start of study treatment.

          -  Women must not be breastfeeding

          -  Women of childbearing potential (WOCBP) must agree to follow instructions for
             method(s) of birth regulation for the duration of treatment with study treatment(s)
             for a total of 5 months post-treatment completion.

        Exclusion Criteria:

          -  Active brain metastases or leptomeningeal metastases. Participants with brain
             metastases are eligible if these have been treated and there is no magnetic resonance
             imaging (MRI except where contraindicated in which CT scan is acceptable) evidence of
             progression for at least 2 weeks after treatment is complete and within 28 days prior
             to first dose of study drug administration. Cases must be discussed with the lead PI,
             Dr. Page. Brain lesions are not considered measurable disease.

          -  Prior malignancy active within the previous 3 years except for locally curable cancers
             that have been apparently cured, such as basal or squamous cell skin cancer, or
             carcinoma in situ of the cervix. Subjects with prior history of unrelated breast
             cancer not requiring active therapy may be considered for enrollment, but require
             discussion with and approval of PI;

          -  Any serious or uncontrolled medical disorder that, in the opinion of the investigator,
             may increase the risk associated with study participation or study drug
             administration, impair the ability of the participant to receive protocol therapy, or
             interfere with the interpretation of study results.

          -  Participants must have recovered from the effects of major surgery requiring general
             anesthetic or significant traumatic injury at least 14 days before enrollment.

          -  Participants with active, known or suspected autoimmune disease. Participants with
             vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
             condition only requiring hormone replacement, psoriasis not requiring systemic
             treatment, or conditions not expected to recur in the absence of an external trigger
             are permitted to enroll.

          -  Participants with a condition requiring systemic treatment with either corticosteroids
             (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within
             14 days of study drug administration. Inhaled or topical steroids and adrenal
             replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of
             active autoimmune disease.

          -  Uncontrolled adrenal insufficiency.

          -  New York Heart Association (NYHA) Functional Classification of Heart Failure: Class
             III or Class IV

          -  All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue
             must have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration
             of study drug. Participants with toxicities attributed to prior anti-cancer therapy
             which are not expected to resolve and result in long lasting sequelae, such as
             peripheral neuropathy grade 2 or less, are permitted to enroll

          -  Known history of positive test for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS).

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, unstable angina pectoris, or psychiatric illness/social situations that
             would limit obtaining informed consent or compliance with study requirements.

          -  Participants who have had a history of acute diverticulitis, intra-abdominal abscess,
             GI obstruction and abdominal carcinomatosis which are known risk factors for bowel
             perforation.

          -  Participants with interstitial lung disease that is symptomatic or may interfere with
             the detection or management of suspected drug-related pulmonary toxicity.

          -  Has known active hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA is
             detected);

          -  History of allergy or hypersensitivity to study drug components

          -  Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
             antibody in the metastatic setting, or any other antibody or drug specifically
             targeting T-cell co-stimulation or checkpoint pathways. Previous treatment with
             anti-PD-1/L1 in the curative setting is allowed if subjects have not received such
             therapy within one year of screening.

          -  Prior treatment with bicalutamide, enzalutamide, or any other androgen receptor
             blocker.

          -  Use of an investigational agent within 4 weeks of Day 1 visit
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:iRECIST Clinical Benefit Rate (the number of patients with objective response or ongoing stable disease at week 24 using iRECIST guidelines)
Time Frame:24 weeks
Safety Issue:
Description:To assess the 24-week clinical benefit rate of nivolumab combined with bicalutamide and ipilimumab in advanced HER2-negative breast cancers according to iRECIST criteria.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Providence Health & Services

Trial Keywords

  • Breast Cancer
  • Her2 negative breast cancer
  • Immunotherapy
  • Opdivo
  • Nivolumab
  • Yervoy
  • Ipilimumab
  • Bicalutamide
  • Casodex

Last Updated