Safety and Preliminary Effectiveness of BNT327, an Investigational Therapy for Breast Cancer, When Given in Combination With Chemotherapy

Inclusion Criteria:

• Have given informed consent by signing and dating an informed consent form beforeinitiation of any study-specific procedures.

• Male or female, aged ≥18 years at the time of giving informed consent.

• Are willing and able to comply with scheduled visits, the treatment schedule, theplanned study assessments (including participant completed diaries) and otherrequirements of the study. This includes that they are able to understand and followstudy-related instructions.

• Have confirmed locally recurrent inoperable or mTNBC as defined by the most recentAmerican Society of Clinical Oncology (ASCO) / College of American Pathologists (CAP) guidelines. Note, participants initially diagnosed with hormonereceptor-positive and/or HER2-positive breast cancer must have histologicalconfirmation of TNBC in a tumor biopsy obtained from a local recurrence or distantmetastasis site.

• Systemic treatment naïve locally advanced/metastatic participants are eligibleif:

• They have received no prior systemic therapy in the locally advancedunresectable/metastatic setting including chemotherapy, immunotherapy, orinvestigational agents.

• They have completed treatment for Stage I-III breast cancer, if indicated,and ≥6 months has elapsed between the completion of treatment withcurative intent (e.g., date of primary breast tumor surgery or date oflast adjuvant chemotherapy administration, or date of last radiationtherapy, whichever occurred last) and first documented local or distantdisease recurrence. This also includes participants initially diagnosedwith hormone receptor-positive and/or HER2-positive breast cancer prior toTNBC diagnosis.

• Participants who received one prior systemic therapy in the locallyadvanced/metastatic setting are eligible if:

• They have received one systemic chemotherapy in the metastatic setting andhave progressed on first line therapy. Radiographic progression must havebeen documented. Radiographic progression is defined as unequivocalprogression of existing tumor lesions or developing new tumor lesions asassessed by the investigator.

• They have had a recurrence-free interval of ≥6 months if they havereceived treatment with curative intent in the past. A recurrence-freeinterval of ≥6 months is required for all participants (both first- andsecond-line treatment settings) who have received prior treatment forbreast cancer with curative intent.

• Have provided a tissue sample, archival or fresh, during the screening period (bonebiopsies, fine needle aspiration biopsies, and samples from pleural or peritonealfluid are not acceptable; participants with only one target lesion are not eligibleto provide a biopsy). If an archival tumor sample is not available, the participantmust undergo a fresh biopsy, if medically feasible to be eligible for the study.

• Have at least one measurable lesion as the targeted lesion based on RECIST version 1.1. Lesions treated after prior local treatment (radiotherapy, ablation,interventional procedures) are generally not considered as target lesions. If thelesion with prior local treatment is the only targeted lesion, evidence-basedradiology must be provided to demonstrate disease progression (the single bonemetastasis or the single central nervous system metastasis should not be consideredas a measurable lesion).

• Eastern Cooperative Oncology Group performance status of 0 or 1.

• Have a minimum life expectancy of >3 months.

• Have adequate organ function, as defined below:

• Hematology:

• Absolute neutrophil count ≥1.5 × 10^9/L (without G-CSF support within twoweeks prior to Cycle 1, Day 1).

• Platelet count ≥100 × 10^9/L (without transfusion within 2 weeks prior toCycle 1, Day 1).

• Hemoglobin ≥90 g/L or 5.6 mmol/L. Note: Criterion must be met withoutpacked red blood cell transfusion or without erythropoietin dependencywithin the prior 2 weeks before receiving the first dose of studytreatment.

• Liver function:

• Total bilirubin ≤1.5 × upper limit of normal (ULN).

• With Gilbert's syndrome total bilirubin <3 mg/dL and direct bilirubin ≤ULN. Note, Gilbert's syndrome must be documented appropriately as pastmedical history.

• Participants without liver metastasis alanine aminotransferase andaspartate aminotransferase ≤2 × ULN.

• Participants with liver metastasis alanine aminotransferase and aspartateaminotransferase ≤5 × ULN.

• Albumin ≥3.0 g/dL.

• Renal function: Creatinine clearance ≥50 mL/min. Cockcroft-Gault formula. Note,in participants who will be treated with gemcitabine plus carboplatin,creatinine clearance should be ≥60 mL/min.

• Qualitative urine protein ≤1+. If qualitative urine protein ≥2+, a 24-hoururine protein quantitative test is required. If the 24-hour urine proteinresult is <1 g, the participant can be enrolled.

• Coagulation function: International normalized ratio or prothrombin time andactivated partial thromboplastin time ≤1.5 × ULN unless the participant isreceiving anticoagulation therapy as long as prothrombin or activated partialthromboplastin is within therapeutic range of intended use of anticoagulant.

• Are women of childbearing potential (WOCBP) who have a negative serum beta humanchorionic gonadotropin pregnancy test. Women who are postmenopausal (defined as 12months with no menses without an alternative medical cause) or permanentlysterilized (verified by medical records) will not be considered WOCBP and thereforewill not be required to undergo pregnancy testing.

• Are WOCBP who agree to practice a highly effective form of contraception and torequire the use of barrier contraception methods, starting at at the time of givinginformed consent and continuously until 6 months after receiving the last studytreatment.

• Are men who are sterile or if they are potentially fertile (i.e., are not surgically [e.g., have had a vasectomy] or congenitally sterile) and sexually active with apartner of childbearing potential, who agree to use condoms and to ask their sexualpartners to practice a highly effective form of contraception during the study,starting at the time of giving informed consent and continuously until 6 monthsafter receiving the last dose of IMP.

• Agree not to donate germ (ova, oocytes, sperm) for the purposes of assistedreproduction during study, starting at the time of giving informed consent andcontinuously until 6 months after receiving the last dose of IMP.

Exclusion Criteria:

• Are pregnant or breastfeeding or are planning pregnancy or planning to fatherchildren during the study or within 6 months after the last dose of IMP.

• Have a medical, psychological, or social condition which, in the opinion of theinvestigator, could compromise their wellbeing if they participate in the study, orthat could prevent, limit, or confound the protocol-specified assessments orprocedures, or that could impact adherence to protocol described requirements.

• Have received any of the following therapies or drugs prior to the initiation ofstudy:

• Participants who received prior treatment with a PD(L)-1/Vascular EndothelialGrowth Factor bispecific antibody.

• Have received a systemic anticancer regimen within 4 weeks prior to theinitiation of study treatment or have received palliative radiotherapy within 7days prior to the initiation of study treatment, or have received any otherchemotherapy, curative/palliative radiotherapy, biologic therapy (includingtumor vaccines, cytokines, or growth factors for tumor control) or anyexperimental antitumor drugs within 4 weeks prior to the initiation of studytreatment.

• Have received other systemic immunostimulatory agents or immunosuppressivetherapies (such as interferon-alpha [IFN-α], interleukin-2 [IL-2], ormethotrexate) within 4 weeks prior to the initiation of study treatment or arewithin five half-lives of the treatment drug (whichever is longer). Exception:Excluding local, intranasal, intraocular, intra-articular or inhaledcorticosteroids, short-term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmuneconditions (e.g., delayed hypersensitivity reactions caused by exposure toallergens).

• Have received systemic corticosteroids (at a dosage greater than 10 mg/day ofprednisone or an equivalent dose of other corticosteroids) within 3 weeks priorto the initiation of study treatment.

• Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior toinitiation of study treatment.

• Received broad-spectrum IV antibiotics therapy within 3 weeks prior toinitiation of study treatment.

• Use of any non-study investigational medicinal product within five half-livesof first dose or within 4 weeks, whichever is longer, before initiation ofstudy treatment in this study or ongoing participation in the active treatmentphase of another interventional clinical study.

• Have undergone major organ surgery (core needle biopsies are allowed >7 days priorstudy start), significant trauma, or invasive dental procedures (such as dentalimplants) within 28 days prior to the initiation of study treatment or plan toundergo elective surgery during the study. Placement of vascular infusion devices isallowed.

• Have received allogeneic hematopoietic stem cell transplantation or organtransplantation.

• Have spinal cord compression or central nervous system metastases that is untreatedand symptomatic or requires treatment with corticosteroids or anticonvulsants forassociated-symptom control. Exception: Treated brain metastases which is no longersymptomatic and for which no corticosteroid or anticonvulsant treatment is needed (the participant must be recovered from the acute toxic effect of radiotherapy;study treatment assignment must be ≥2 weeks after completion of radiotherapy).

• Have active autoimmune disease that has required systemic treatment in the past 2years (e.g., with use of disease modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency) is not considered a form of systemic treatment. Those who had ahistory of autoimmune diseases with anticipated relapse (such as systemic lupuserythematosus, rheumatoid arthritis, vasculitis, etc.), except for those withclinically stable autoimmune thyroid disease or type 1 diabetes.

• Have had other malignant tumors within 2 years prior to the study treatment are notallowed. Except for those: who have been cured with local treatment (such as basalcell or squamous cell carcinoma of the skin, superficial or non-invasive bladdercancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, andpapillary carcinoma of thyroid; including prostate cancer with CR within the past 3years).

• Have any of the following heart conditions within 6 months prior to the studytreatment:

• Acute coronary syndrome, coronary artery bypass grafting, congestive heartfailure, aortic dissection, stroke, or other Grade 3 and above cardiovascularand cerebrovascular events.

• New York Heart Association functional classification ≥II heart failure or leftventricular ejection fraction <50%.

• Those who have ventricular arrhythmias requiring clinical intervention, second-to third-degree atrioventricular block, or congenital long QT syndrome.Participants with treated cardiac arrythmia/atrial fibrillation are allowed.

• Mean QT interval corrected by Fridericia's method (QTcF) >480 ms (the ECG canbe repeated at the discretion of the investigator).

• Use of cardiac pacemaker.

• Cardiac troponin I or T >2 x ULN.

• Have any of the following hypertension or diabetic conditions prior to initiation ofstudy treatment:

• Poorly controlled diabetes (fasting blood glucose ≥13.3 mmol/L [240 mg/dL] orHbA1C [≥8.5%]).

• Uncontrolled hypertension (systolic blood pressure ≥150 mmHg and/or diastolicblood pressure ≥90 mmHg) while on antihypertensive medicine.

• A history of hypertensive crisis or hypertensive encephalopathy.

• Have serious non-healing wounds, ulcers, or bone fractures. This includes history ofabdominal fistula, tracheoesophageal fistula, gastrointestinal perforation, or intraabdominal abscess for which an interval of 6 months must pass before the ScreeningVisit. In addition, the participant must have undergone correction (or spontaneoushealing) of the perforation/fistula and/or the underlying process causing thefistula/perforation.

• Participants with evidence of major coagulation disorders or other significant risksof hemorrhage such as:

• History of intracranial hemorrhage or intraspinal hemorrhage.

• Tumor lesions invading large blood vessels and are at significant risk ofbleeding.

• Had clinically significant hemoptysis or tumor hemorrhage of any cause within 1month prior to the initiation of study treatment.

• Have uncontrolled pleural effusion, pericardial effusion, or ascites requiringrecurrent drainage procedures (once monthly or more frequently). Participants withindwelling catheters (e.g., PleurX) are allowed.

• Have uncontrolled tumor-related pain requiring analgesic treatment not managed by astable analgesic regimen. For asymptomatic metastatic lesion, if its growth maycause dysfunction or intractable pain (e.g., current epidural metastasis unrelatedto spinal cord compression), local treatment should be considered before screening,if appropriate.

• Have a known or suspected hypersensitivity to the study treatments including anyactive ingredient or excipients thereof.

• Have a known human immunodeficiency virus infection or known acquiredimmunodeficiency syndrome, with the following exceptions:

• Participants with cluster of differentiation 4 (CD4)+ T-cell (CD4+) counts ≥350cells/µL per local laboratory should generally be eligible for the study.

• Participants who have not had an opportunistic infection within the past 12months.

• Have a known history/positive serology for hepatitis B requiring active antiviraltherapy (unless immune due to vaccination or resolved natural infection or unlesspassive immunization due to immunoglobulin therapy). Individuals with positiveserology must have hepatitis B virus viral load below the limit of quantification.

• Have active hepatitis C virus infection; individuals who have completed curativeantiviral treatment with hepatitis C virus viral load below the limit ofquantification are allowed.

• Are subject to exclusion periods from another investigational study.

• Are vulnerable individuals, i.e., are individuals whose willingness to volunteer ina clinical study may be unduly influenced by the expectation, whether justified ornot, of benefits associated with participation, or of a retaliatory response fromsenior members of a hierarchy in case of refusal to participate. This includes allsponsor, study site, or third party (e.g., CRO, vendor) personnel directly involvedin the conduct of the study and their family members or dependents, as well as allstudy site personnel otherwise supervised by the investigator.

• Participants with AEs from prior antitumor therapy that have not returned to Grade 1 (graded by NCI CTCAE version 5.0 criteria) or below (unless the investigatordetermines that certain AEs pose no safety risk to participants, such as hair loss,Grade 2 peripheral neuropathy or stable hypothyroidism under hormone replacementtherapy) are not eligible for the study.

• Have superior vena cava syndrome or symptoms of spinal cord compression.

• Those with active, or a history of, pneumonitis requiring treatment with steroids,or has active, or a history of, interstitial lung disease. Those with a history ofpulmonary fibrosis, or currently diagnosed with severe lung diseases such asinterstitial pneumonia, pneumoconiosis, chemical pneumonitis, or any other conditionresulting in significant impairment in lung function. Exception: Asymptomaticinterstitial changes caused by previous radiation therapy, chemotherapy, or otherfactors such as smoking are acceptable.

• Have active tuberculosis or history of tuberculosis that was not successfullytreated.

• Have underlying condition(s) that may increase risk of the combination treatment orcomplicate the interpretation of toxicities and AEs, as judged by the investigator,or other scenarios that the investigators consider the participant is not eligiblefor the study.