INCMGA00012 and Pelareorep for the Treatment of Metastatic Triple Negative Breast Cancer, IRENE Study

Inclusion Criteria:

• Metastatic or inoperable locally advanced, histologically documented triple negativebreast cancer (TNBC) (negative expression of estrogen receptor [ER], progesteronereceptor [PR] and human epidermal growth factor receptor 2 [HER2]immunohistochemistry [IHC] 0 or 1+, HER2 fluorescence in situ hybridization [FISH]negative if IHC 2+, per American Society of Clinical Oncology [ASCO] College ofAmerican Pathologists [CAP] guidelines)

• Pre-menopausal and post-menopausal women who have received 1-2 prior lines ofsystemic therapy for metastatic triple negative breast cancer. Patients must havereceived at least one prior line of chemotherapy

• Patients who have received adjuvant therapy for locally advanced triple negativebreast cancer may be eligible for the study if they relapse with metastatic diseasewithin 6 months since completion of neo-adjuvant/adjuvant systemic therapy. Theadjuvant/neoadjuvant therapy will be considered as 1 line of therapy

• Availability of tumor specimen for determination of PD-L1 and additional biomarkerstudies. Patient should be willing to undergo a pre-treatment biopsy as well as abiopsy after cycle 2 to evaluate the tumor microenvironment

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

• Patients who have received prior treatment with anti-PD-1 or anti-PD-L1 inhibitorsare eligible for the study

• Absolute neutrophil count >= 1,000/uL

• Platelet count >= 100,000/uL

• Hemoglobin >= 9.0 g/dL

• Total bilirubin =< 2 x upper limit of normal (ULN) or =< 3 x ULN for subjects withGilbert's disease or liver metastases

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (=< 5x ULN if evidence of hepatic involvement by malignant disease)

• Estimated glomerular filtration rate (eGFR) >= 40 mL/min/1.73m^2

• Lactate dehydrogenase (LDH) < 2 x ULN

• Provision of signed and dated informed consent form

• Life expectancy >= 3 months, as determined by the investigator

• Patients must have clinically and/or radiographically documented measurable disease.At least one site of disease must be uni-dimensionally measurable as per ResponseEvaluation Criteria in Solid Tumors (RECIST) version (v)1.1

• For patients receiving therapeutic anticoagulation: stable anticoagulant regimenduring the 14 days prior to initiation of study treatment

• Subjects with central nervous system (CNS) metastases treated with radiation therapy (whole-brain radiation therapy [WBXRT] or stereotactic radiosurgery [SRS]) areeligible if, > 28 days following completion of radiation therapy (XRT), they showstable disease on post-treatment magnetic resonance imaging (MRI)/computedtomography (CT), are off corticosteroids, and are neurologically stable

• Female patients of childbearing potential have a negative pregnancy test atbaseline. Females of childbearing potential are defined as sexually mature womenwithout prior hysterectomy or who have had any evidence of menses in the past 12months. However, women who have been amenorrheic for 12 or more months are stillconsidered to be of childbearing potential if the amenorrhea is possibly due toprior chemotherapy, anti estrogens, or ovarian suppression

• Patients who are not postmenopausal (>= 12 months of non-therapy-inducedamenorrhea) or surgically sterile must have a negative urine pregnancy test (positive urine tests are to be confirmed by serum test) documented within 14days of treatment initiation

• Sexually active women of childbearing potential enrolled in the study mustagree to use 2 forms of accepted methods of contraception during the course ofthe study and for 12 weeks after their last dose of study drug. Effective birthcontrol includes (a) intrauterine device plus 1 barrier method; (b) on stabledoses of hormonal contraception for at least 3 months (e.g., oral, injectable,implant, transdermal) plus one barrier method; (c) 2 barrier methods. Effectivebarrier methods are male or female condoms, diaphragms, and spermicides (creamsor gels that contain a chemical to kill sperm); or (d) a vasectomized partner

Exclusion Criteria:

• Subjects who have received 4 or more lines prior treatment in the metastatic setting

• Has active autoimmune disease that has required systemic treatment in the past 2years (i.e., with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs) or a documented history of clinically severe autoimmunedisease, or a syndrome that requires systemic steroids or immunosuppressive agents.Vitiligo, alopecia, hypothyroidism only requiring hormone replacement, psoriasis notrequiring systemic treatment, celiac disease controlled by diet alone or conditionsnot expected to recur in the absence of an external trigger are permitted

• History of psychiatric illness or social situations that would limit compliance withstudy requirements. Has a history or current evidence of any condition, therapy, orlaboratory abnormality that might confound the results of the trial, interfere withthe subject's participation for the full duration of the trial, or is not in thebest interest of the subject to participate, in the opinion of the treatinginvestigator

• Known active, untreated central nervous system (CNS) metastases and/or carcinomatousmeningitis except for patients with =< 3 small (< 0.6 cm) asymptomatic brain lesionswhere treatment is not indicated. Patients with neurological symptoms must undergo ahead computed tomography (CT) scan or brain magnetic resonance imaging (MRI) toexclude brain metastasis

• Subjects previously treated with pelareorep

• Evidence of interstitial lung disease, history of interstitial lung disease, oractive, noninfectious pneumonitis

• Prior allogeneic stem cell or solid organ transplantation

• Patients may not have non-oncology vaccine therapies for prevention of infectiousdisease (for example, seasonal live influenza vaccine, human papilloma virusvaccine) within 4 weeks of study drug administration. Vaccination while on study isalso prohibited except for administration of the inactivated influenza vaccine

• Known history of human immunodeficiency virus (HIV) or other seriousimmunocompromised state

• Known positive hepatitis B surface antigen undergoing anti-viral treatment and/oractive hepatitis C indicated by positive quantitative hepatitis C virus (HCV)ribonucleic acid (RNA)

• Patient is pregnant or breastfeeding

• Receipt of any investigational treatment or anti-cancer therapy within 14 days ofenrollment into the study

• Known hypersensitivity to the study drugs or their components

• Documented history of a cerebral vascular event (stroke or transient ischemicattack), unstable angina, myocardial infarction, or cardiac symptoms consistent withNew York Heart Association (NYHA) class III-IV within 6 months prior to their firstdose of study drugs

• Prior malignancies (except non-melanoma skin cancers, and the following in situcancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, orbreast) unless a complete remission was achieved at least 1 year prior to studyentry

• Active alcohol or drug abuse per treating physician

• Patients may not participate in any other therapeutic clinical trials, includingthose with other investigational agents not included in this trial, throughout theduration of this study

• Toxicity of prior therapy that has not recovered to =< grade 1 or baseline (with theexception of any grade of alopecia and anemia not requiring transfusion support)

• For patients who have received prior immune-checkpoint therapy: Immune-relatedtoxicity during prior checkpoint inhibitor therapy for which permanentdiscontinuation of therapy was recommended (per product label or consensusguidelines), OR any immune-related toxicity that required intensive or prolongedimmunosuppression. (With the exception of endocrinopathy that is well controlled onreplacement hormones)