Ipilimumab and Nivolumab in Treating Patients With Recurrent Stage IV HER2 Negative Inflammatory Breast Cancer

PRIMARY OBJECTIVES:

I. To determine progression free survival (PFS) in patients with newly recurrent HER2
negative inflammatory breast cancer (IBC) treated with nivolumab and ipilimumab according to
Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.

SECONDARY OBJECTIVES:

I. To assess the overall response rate (ORR) and clinical benefit rate (CBR) according to
RECIST criteria v1.1, in patients with recurrent IBC treated with nivolumab and ipilimumab.

II. To assess overall survival in patients with recurrent HER2 negative IBC treated with
nivolumab and ipilimumab.

III. To assess the safety and tolerability of nivolumab and ipilimumab in patients with
recurrent IBC according to the National Cancer Institute Common Terminology Criteria for
Adverse Events v 4.03.

TERTIARY OBJECTIVES:

I. To assess the predictive value of baseline iSCORE and programmed cell death 1 ligand 1
(PDL-1) expression using archival tissue samples as well as any standard of care tissue
obtained during study treatment.

II. To assess the predictive value of circulating cell-free tumor DNA (ctDNA) and immune
signature by exosome analysis using blood samples at baseline.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes every 2 weeks (Q2W) and
ipilimumab IV over 90 minutes every 6 weeks (Q6W) in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 weeks for 12 weeks, and
then every 3 months for up to 2 years.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed stage IV breast carcinoma
with a previous clinical diagnosis of IBC based on the presence of inflammatory
changes in the involved breast, such as diffuse erythema and edema (peau d'orange),
with or without an underlying palpable mass involving the majority of the skin of the
breast; pathological evidence of dermal lymphatic invasion should be noted but is not
required for diagnosis

- Patients must have local or metastatic recurrence of IBC after prior surgery

- Patients must have a metastatic tumor negative for HER2; the lack of HER2
overexpression by immunohistochemistry (IHC), is defined as 0 or 1+ where as
hyperexpression is defined as 3+; if equivocal IHC, 2+, the tumor must be non-gene
amplified by fluorescence in situ hybridization (FISH) performed upon the primary
tumor or metastatic lesion (ratio < 2 and HER2 copy number < 4)

- Patients may have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension in accordance with RECIST criteria v.
1.1 OR non-measurable tumors; NOTE: Non-measurable tumors are small lesions (longest
diameter < 10mm or pathological lymph nodes with >= 10 to < 15 mm short axis); bone
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by
computed tomography [CT] or magnetic resonance imaging [MRI]) are considered as
non-measurable

- Patients must be in consideration for 1st line systemic therapy for recurrent IBC;
NOTE: Patients must not have received chemotherapy in the metastatic setting, but
adjuvant treatment after surgery is acceptable

- Patients must have confirmed availability of archival or freshly biopsied tumor tissue
meeting protocol-defined specifications prior to study enrollment

- Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) status of 0-1; ECOG
performance status 2 and 3 will be allowed only if decline in performance status is
thought to be directly secondary to breast cancer disease burden by treating physician

- Patients must have adequate organ and bone marrow function within 14 days prior to
registration, as defined below:

- Leukocytes >= 2,000/mcL

- Absolute neutrophil count >= 1,500/mcL, regardless of transfusion or growth factor
support

- Platelets >= 100,000/mcl, regardless of transfusion or growth factor support

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients
with Gilbert syndrome or liver metastasis who can have total bilirubin < 3.0 x ULN)

- Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/
alanine aminotransferase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
upper limit of normal (ULN) (or =< 5 times ULN in case of liver metastasis)

- Serum creatinine of < 3.0 x ULN (upper limit of normal)

- Patients with history of central nervous system (CNS) metastases are eligible if CNS
disease has been stable for at least 6 weeks prior to study registration in the
opinion of the investigator and do not require corticosteroids (of any dose) for
symptomatic management; NOTE: Patients are not required to have CNS imaging prior to
study entry

- Females of childbearing potential (FOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic
gonadotropin [HCG]) within 72 hours of registration

NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone a tubal
ligation, or remaining celibate by choice) who meets the following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy

- Has had menses at any time in the preceding 12 consecutive months (and therefore has
not been naturally postmenopausal for > 12 months)

- FOCBP and men who are sexually active with FOCBP must agree to follow
instructions for method(s) of contraception for the duration of treatment and the
designated post-treatment period

- Patients must have the ability to understand and the willingness to sign a
written informed consent prior to registration on study

Exclusion Criteria:

- Patients must not have had chemotherapy or radiotherapy within 4 weeks prior to study
registration

- Patients who already received chemotherapy for recurrent metastatic IBC are not
eligible

- Patients who have not recovered to =< grade 1 from adverse events due to agents
administered more than 4 weeks earlier are not eligible

- Patients may not be receiving any other investigational agents

- Patients who have had prior exposure to immune checkpoint inhibitors are not eligible;
please contact principal investigator, Ricardo Costaat 312-472-1234 for specific
questions on potential interactions

- Programmed cell death protein 1 (PD-1) monoclonal antibody: pembrolizumab,
pidilizumab, MEDI-0680, anti-PD-1 fusion protein AMP-224 (AMP-224), anti-PD-1
checkpoint inhibitor PF-06801591 (PF-06801591), anti-PD-1 monoclonal antibody
BGB-A317 (BGB-A317), anti-PD-1 monoclonal antibody PDR001 (PDR001), anti-PD-1
monoclonal antibody REGN2810 (REGN2810), anti-PD-1 monoclonal antibody SHR-1210
(SHR-1210)

- PD-L1 monoclonal antibody: durvalumab, avelumab, anti-PD-L1 monoclonal antibody
MDX-1105 (MDX-1105), atezolizumab, zirconium Zr 89-labeled anti-PD-L1 monoclonal
antibody MPDL3280A (MPDL3280A)

- Cytotoxic T-lymphocyte protein 4 (CTLA4) monoclonal antibody: tremelimumab,
abatacept

- Tumor necrosis factor receptor superfamily member 4 (OX40): agonistic anti-OX40
monoclonal antibody MEDI6383 (MEDI6383), agonistic anti-OX40 monoclonal antibody
MEDI6469 (MEDI6469), anti-OX40 monoclonal antibody MEDI0562 (MEDI0562), oxelumab,
anti-OX40 antibody PF-04518600 (PF-04518600)

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including chronic prolonged systemic corticosteroids (defined as corticosteroid use of
duration one month or greater), should be excluded; these include but are not limited
to patients with a history of:

- Immune related neurologic disease

- Multiple sclerosis

- Autoimmune (demyelinating) neuropathy

- Guillain-Barre syndrome

- Myasthenia gravis

- Systemic autoimmune disease such as systemic lupus erythematosus (SLE)

- Connective tissue diseases

- Scleroderma

- Inflammatory bowel disease (IBD)

- Crohn's

- Ulcerative colitis

- Patients with a history of toxic epidermal necrolysis (TEN)

- Stevens-Johnson syndrome

- Anti-phospholipid syndrome

- NOTE: Subjects 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

- Patients who have an uncontrolled intercurrent illness including, but not limited to
any of the following, are not eligible:

- Ongoing or active infection (including minor localized infections) requiring oral
or IV treatment

- Symptomatic congestive heart failure, defined as a clinical syndrome resulting
from any structural or functional cardiac disorder that impairs the ability of
the ventricle to fill with or eject blood

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would limit compliance with study
requirements

- Any other illness or condition that the treating investigator feels would
interfere with study compliance or would compromise the patient's safety or study
endpoints

- Patients should not have any condition requiring systemic treatment with
corticosteroids (< 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days prior to first dose of study drug; NOTE: Inhaled or topical
steroids and adrenal replacement steroid doses < 10 mg daily prednisone equivalents
are permitted in the absence of active autoimmune disease; a brief (less than 3 weeks)
course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment
of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by a
contact allergen) is permitted

- Female patients who are pregnant or nursing are not eligible

- No other prior malignancy is allowed except for the following:

- Adequately treated basal cell or squamous cell skin cancer

- In situ cervical cancer

- Or any other cancer from which the patient has been disease free for at least
three years

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS) is not permitted

- Any known positive test for hepatitis B or hepatitis C virus indicating acute or
chronic infection is not permitted

- Patients who have received a live attenuated vaccine within 30 days are not eligible