NIMBUS: A Phase II Study of Nivolumab Plus Ipilimumab in Metastatic Hypermutated HER2-negative Breast Cancer

• 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.