NIMBUS: A phase II study of nivolumab plus ipilimumab in metastatic hypermutated HER2-negative breast cancer

This research study is studying a drug combination of nivolumab and ipilimumab as a possible
treatment for hypermutated HER2 negative breast cancer.

The drugs involved in this study are:

- Nivolumab (Opdivo ®)

- Ipilimumab (Yervoy ®)

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed invasive breast
cancer, with metastatic disease. Participants without pathologic or cytologic
confirmation of metastatic disease should have unequivocal evidence of metastasis from
physical examination or radiologic evaluation.

- Breast cancer must be HER2-negative by IHC or non-amplified as determined by the
current ASCO-CAP criteria. If patient has more than one histological result, the most
recent one will be usedfor inclusion. Participants may be ER/PR positive or negative.

- Patients must harbor tumors with total mutational burden (TMB) of at least 9 mutations
per megabase assessed by a cancer-gene panel containing more than 300 genes, and
performed in a CLIA verified laboratory. Tests like Foundation One, Oncopanel (DFCI),
or IMPACT (MSKCC) are acceptable for including patients on this trial.

- Participants must have measurable disease by RECIST version 1.1.

- Participants must agree to undergo a research biopsy, if tumor is safely accessible,
at baseline and at day 29 cycle 1 (+14 scheduling window). Previously collected
archival tissue will be obtained on all participants. Participants for whom
newly-obtained samples cannot be provided (e.g. inaccessible or participant safety
concern) may submit an archived specimen (block or if not possible, 20 unstained
slides).

- Prior chemotherapy: Participants may have received 0-3 prior chemotherapeutic regimens
for metastatic breast cancer and must have been off treatment with chemotherapy for at
least 14 days prior to study treatment initiation.

- Patients with hormone receptor positive breast cancer must have progressed on at least
one prior line of endocrine therapy in the metastatic setting or have disease
recurrence while on adjuvant endocrine therapy.

- Participants should also be adequately recovered from acute toxicities of prior
treatment, with the exception of alopecia and peripheral sensory neuropathy.

- Prior biologic therapy: Patients must have discontinued all biologic therapy at least
14 days prior to study treatment initiation.

- Prior radiation therapy: Patients may have received prior radiation therapy in either
the metastatic or early-stage setting. Radiation therapy must be completed 14 days
prior to study treatment initiation.

- In all cases, there must be no ongoing complications from prior radiotherapy.

- The subject is ≥18 years old.

- ECOG performance status ≤1(Karnofsky ≥70%, see Appendix A).

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count ≥1,000/mcL

- platelets ≥100,000/mcL

- hemoglobin ≥ 8 g/dl

- total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤ 2.0 x ULN
in patients with documented Gilbert's Syndrome)

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or (≤ 3 × institutional ULN for
participants with documented liver metastases)

- creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 40 mL/min (using
Cockcroft-Gault formula) for participants with creatinine levels above
institutional ULN.

- Female subjects of childbearing potential must have a negative pregnancy test (serum
or urine) at screening.

- Childbearing potential is defined as: participants who have not reached a
postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause
other than menopause) and has not undergone surgical sterilization (removal of ovaries
and/or uterus).

- Female and male participants of childbearing potential must agree to use an adequate
method of contraception. For women, contraception is required starting with the first
dose of study medication through 150 days (5 months) after the last dose of study
medication. For men who are sexuall active with women of childbearing potential,
contraception is required starting with the first dose of study medication for a
period of 7 months after the last dose of nivolumab. Examples of contraceptive methods
with a failure rate of < 1% per year include bilateral tubal ligation, male
sterilization, established and proper use of hormonal contraceptives that inhibit
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the duration
of the clinical trial and the preferred and usual lifestyle of the patient. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
withdrawal are not acceptable methods of contraception.

- Participants on bisphosphonates may continue receiving bisphosphonate therapy during
study treatment. Initiation of bisphosphonate or RANKL agent is allowed on study.

- The participant is capable of understanding and complying with the protocol and has
signed the informed consent document.

Exclusion Criteria:

- Major surgery within 2 weeks before the first dose of study treatment.

- Concurrent administration of other anti-cancer therapy within 14 days of starting
protocol therapy and during the course of this study.

- The participant has received another investigational agent within 14 days of the first
dose of study drug.

- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody.

- Known brain metastases that are untreated, symptomatic, or require therapy to control
symptoms. Participants with a history of treated central nervous system (CNS)
metastases are eligible. Treated brain metastases are defined as those having no
evidence of progression for ≥ 2 weeks after treatment, and no ongoing requirement for
corticosteroids, as ascertained by clinical examination and brain imaging (magnetic
resonance imaging or CT scan) completed during screening. Subject must be either off
corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily (or equivalent)
for at least 7 days prior to first study treatment. Treatment for brain metastases may
include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate
by the treating physician. Participants with CNS metastases treated by neurosurgical
resection or brain biopsy performed within 28 days before study treatment initiation
will be excluded.

- The subject has uncontrolled, significant intercurrent or recent illness. Individuals
with a history of different malignancy are ineligible except for the following
circumstances. Individuals with a history of other malignancies are eligible if they
have been disease-free for at least 3 years or are deemed by the investigator to be at
low risk for recurrence of that malignancy.

- Participant has an active infection requiring IV antibiotics at initiation of study
therapy.

- Patient has a medical condition that requires chronic systemic steroid therapy or on
any other form of immunosuppressive medication. For example, participants with
autoimmune disease that requires systemic steroids or immunosuppression agents should
be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic treatment.

- Subjects with current pneumonitis, or requiring supplementary O2 therapy.

- The participant is known to be positive for human immunodeficiency virus (HIV),
HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy
are ineligible

- Participants with any other active malignancy requiring concurrent intervention.

- Known hypersensitivity to any of the components of ipilimumab or nivolumab.

- The participant has received a live vaccine within 28 days prior to the first dose of
trial treatment and while participating in the trial. Examples of live vaccines
include, but are not limited to, the following: measles, mumps, rubella,
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The use of the
inactivated seasonal influenza vaccine (Fluzone®) is allowed.

- The participant is pregnant or breastfeeding.