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
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
- ECOG performance status of 0-1;
- Metastatic or locally advanced unresectable HER2-negative breast cancer (by NCCN
- 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
- 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.
- 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
- 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
- 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
- Use of an investigational agent within 4 weeks of Day 1 visit