Ipilimumab and Nivolumab in Treating Patients With Recurrent Stage IV HER2 Negative Inflammatory Breast Cancer
Condition: HER2/Neu Negative; Recurrent Inflammatory Breast Carcinoma; Stage IV Breast Cancer; Stage IV Inflammatory Breast Carcinoma
MeSH terms: Carcinoma; Breast Neoplasms; Inflammatory Breast Neoplasms; Recurrence
Intervention: Ipilimumab; Laboratory Biomarker Analysis; Nivolumab
Intervention description: Given IV; Correlative studies; Given IV
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of this research study is to look at the efficacy (the effect on tumor) and the
      safety (the effect on body) of the study drugs when given as a combination in patients with
      metastatic recurrent epidermal growth factor receptor 2 (HER2) negative inflammatory breast
      cancer. This is a phase II study of 2 drugs used in combination: nivolumab and ipilimumab.
      The combination of these drugs is already approved by the Food and Drug Administration (FDA)
      to treat advanced melanoma (a type of skin cancer). Nivolumab and ipilimumab are not approved
      by the FDA for patients with metastatic recurrent HER2 negative inflammatory breast cancer,
      hence the treatment is considered experimental or investigational.
    

Eligibility criteria:

        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