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

  • End date
    Apr 25, 2025
  • participants needed
  • sponsor
    Providence Health & Services
Updated on 25 January 2021
measurable disease
breast cancer
growth factor
gilbert's syndrome
systemic chemotherapy
triple negative breast cancer
epidermal growth factor
her2/neu-negative breast cancer


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.


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.

Condition Ductal Carcinoma In Situ, Breast Cancer, Breast Cancer Diagnosis, Breast Neoplasm Female, Ductal Carcinoma In Situ (DCIS), breast carcinoma, cancer, breast, breast tumors, tumor of the breast, breast tumor
Treatment bicalutamide, Ipilimumab, Nivolumab
Clinical Study IdentifierNCT03650894
SponsorProvidence Health & Services
Last Modified on25 January 2021


Yes No Not Sure

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): WBC2000/L; Neutrophils1500/L; Platelets100 103/L; Hemoglobin 9.0 g/dL; AST3 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
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