Safety and Preliminary Efficacy of BNT314 in Cancer Patients With Malignant Solid Tumors

Inclusion Criteria:

1. Have the ability to voluntarily give informed consent by signing and dating theinformed consent form (ICF) before initiation of any study-specific procedures.

2. Are willing and able to comply with scheduled visits, treatment schedule, laboratorytests, lifestyle restrictions, and other requirements of the study. This includesthat they are able to understand and follow study-related instructions.

3. Are ≥18 years of age at the time of giving informed consent.

4. Have measurable disease according to RECIST v1.1.

5. Have a life expectancy of >3 months.

6. Have Eastern Cooperative Oncology Group Performance Status score of 0 or 1 atscreening.

7. Have adequate coagulation function at screening as determined by:

• International normalized ratio or prothrombin time ≤1.5 × upper limit normal (ULN; unless on therapeutic anticoagulants with values within therapeuticwindow).

• Activated partial thromboplastin time ≤1.5 × ULN (unless on therapeuticanticoagulants with values within therapeutic window).

8. Have adequate bone marrow/hematologic function at screening as determined by:

• Absolute neutrophil count (ANC) ≥1.5 × 10^9/L (≥1500/μL) (patients may not usegranulocyte colony stimulating factor or granulocyte-macrophage colonystimulating factor to achieve these ANC levels in the past 7 days).

• Platelet count ≥100 × 10^9/L (≥100,000/μL).

• Hemoglobin ≥9 g/dL.

• Any blood transfusions ≤28 days before first dose of study treatment should bedocumented.

9. Have adequate hepatic function at screening as determined by:

• Total bilirubin (Tbili) ≤1.5 × ULN OR direct bilirubin ≤ULN for patients withTbili levels >1.5 × ULN. Patients with Gilbert's syndrome must have a Tbili <3mg/dL and direct bilirubin ≤ULN.

• Alanine aminotransferase and aspartate aminotransferase ≤2.5 ULN for patientswith or without liver metastases.

• Albumin ≥30 g/L.

10. Have adequate renal function at screening as determined by glomerular filtrationrate ≥45 mL/min/1.73 m^2 according to the abbreviated Modification of Diet in RenalDisease equation.

11. Have adequate pancreas function at screening as determined by amylase and lipasewith no signs and symptoms of pancreatitis.

12. Patients of childbearing potential (POCBP) must have a negative urine or blood betahuman chorionic gonadotropin test at screening. Patients that are postmenopausal orpermanently sterilized (verified by medical records) will not be considered POCBP,and therefore are not required to undergo pregnancy testing.

13. POCBP must agree to practice a highly effective form of contraception and to requiretheir male partners to use condoms coated with a spermicidal agent, starting atVisit D1 and thereafter until 120 days after receiving the last study treatment.

14. POCBP must agree not to donate eggs (ova, oocytes) for the purposes of assistedreproduction during study, starting at Visit D1 and thereafter until 120 days afterreceiving the last study treatment.

15. Males who are sexually active and have not had a bilateral vasectomy or orchidectomymust agree to use condoms coated with a spermicidal agent and to require theirfemale partners to practice a highly effective form of contraception during thestudy, starting at Visit D1 and thereafter until 120 days after receiving the laststudy treatment.

16. Males must be willing to refrain from sperm donation, starting at Visit D1 andthereafter until 120 days (one sperm cycle) after receiving the last studytreatment.

17. Patients must have a histologically confirmed advanced malignant solid tumor, havingexperienced disease progression on or after standard therapy, or were intolerant ofor not eligible for standard therapy.

Other inclusion criteria specific to selected tumor indications may apply.

Exclusion Criteria:

1. Patients that have uncontrolled intercurrent illness, including but not limited to:

• Ongoing or active infection requiring treatment with anti-infective therapyadministered less than 2 weeks prior to first dose.

• Symptomatic congestive heart failure (Grade III or IV as classified by the NewYork Heart Association), unstable angina pectoris, or symptomatic untreatedcardiac arrhythmia. Treated and/or asymptomatic cardiac arrythmia/atrialfibrillation will be allowed.

• History of arterial thrombosis or pulmonary embolism within 6 months before thefirst dose of study treatment.

• History of myocardial infarction within 6 months before the first dose of studytreatment.

• Uncontrolled hypertension defined as systolic blood pressure ≥160 mm Hg and/ordiastolic blood pressure ≥100 mm Hg, despite optimal medical management.

• Prolonged QTc interval at baseline of ≥470 milliseconds using Fridericia's QTcorrection formula.

• Ongoing or recent (within one year of screening) evidence of significantautoimmune disease that required treatment with systemic immunosuppressivetreatments, which may suggest risk for immune-related adverse events (irAEs).

• History of:

• Grade 2 immune-mediated myocarditis/colitis/pneumonitis that led tocheckpoint inhibitor (CPI) discontinuation. Patients experiencing otherGrade 2 immune-mediated AEs that led to CPI discontinuation, requirediscussion with the sponsor.

• Any Grade ≥3 immune-mediated AEs that led to CPI discontinuation.

• Patients with Grade 3 AEs that led to CPI discontinuation but resolvedwithin 21 days without sequalae may also be considered for discussion withthe sponsor.

• History of chronic liver disease (e.g., alcoholic hepatitis or nonalcoholicsteatohepatitis, drug-related or autoimmune hepatitis) or evidence of hepaticcirrhosis.

• History of non-treated intracerebral arteriovenous malformation (shunts),non-treated cerebral aneurysm, spinal cord compression (from disease),carcinomatous meningitis, or stroke will be excluded.

• History of acute or chronic pancreatitis of any etiology within 6 weeks priorto the start of study treatment.

• Ongoing pneumonitis or history of noninfectious pneumonitis that has requiredsteroids or evidence of interstitial lung disease.

• Transient ischemic attack less than one month prior to screening will beexcluded.

• History of brain/central nervous system (CNS) metastases. Patients with newlyidentified or known unstable or symptomatic CNS metastases will be excluded.Patients with previously treated brain metastases are allowed provided lesionsare radiologically stable (i.e., without evidence of progression) for at least 28 days by repeat imaging, latest imaging performed maximum 6 weeks prior toCycle 1, Day 1.

• Serious, non-healing wound, skin ulcer (of any grade), or bone fracture will beexcluded.

• Other concurrent severe and/or uncontrolled medical condition that would, inthe investigator's judgment, contraindicate patient participation in thisclinical study (e.g., acute or chronic pancreatitis, active hepatitis). Knownprimary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T-cellnegative severe combined immunodeficiency [SCID] or combined T- and B-cellimmunodeficiencies (e.g., T- and B-cell negative SCID, Wiskott Aldrichsyndrome, ataxia telangiectasia, common variable immunodeficiency).

• Major surgery within 3 weeks before signature of the ICF unless fully recoveredfrom the surgery in the opinion of the investigator.

• Any positive test for hepatitis B (defined as positive for hepatitis B surfaceantigen [HBsAg] or hepatitis B virus DNA), indicating acute or chronicinfection.

• Any positive test for hepatitis C (defined as positive for hepatitis C virusantibody or hepatitis C virus RNA), indicating acute or chronic infection.

2. Prior therapy:

• Radiotherapy within 14 days prior to first BNT314 administration. Palliativeradiotherapy will be allowed, but not to target lesions.

• Any epithelial cell adhesion molecule- or 4-1BB-targeting treatment.

• Treatment with an anticancer agent within 4 weeks or for systemic therapiesafter at least five half-lives of the drug, whichever is shorter, prior tostudy treatment administration.

• Patient has received any investigational agent (including investigationalvaccines) or used an invasive investigational medical device within 28 daysbefore the planned first dose of BNT314 or is currently enrolled in an (another) interventional study. Patients who are in the follow-up phase of aninterventional study may participate if they have not received aninvestigational agent within 28 days (or five half-lives, whichever is longer)of the first dose of BNT314.

• Patient has a condition requiring systemic treatment with eithercorticosteroids (>10 mg daily prednisone or equivalent) or otherimmunosuppressive medications within 14 days of the first dose of BNT314.Inhaled or topical steroids, and adrenal or pituitary replacement steroid >10mg daily prednisone or equivalent, are permitted in the absence of activeautoimmune disease.

• Patient has received granulocyte or granulocyte/macrophage colony stimulatingfactor (G-CSF/GM-CSF) support within 4 weeks prior to first BNT314administration or is chronically transfusion dependent; G-CSF and otherhematopoietic factors may be used in the management of acute toxicity (such asfebrile neutropenia) or prophylactically, when clinically indicated at theinvestigator's discretion.

• Received any live vaccine within 30 days prior to the start of study treatment.

3. Known alcohol dependency within 6 months enrollment in this study.

4. Planned enrollment in another study of an IMP, starting after Visit D1 andcontinuously until the last planned visit in this study.

5. 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.

6. Are subject to exclusion periods from another investigational study.

7. Are vulnerable individuals as per International Council for Harmonisation E6definition, i.e., are individuals whose willingness to participate in a clinicalstudy may be unduly influenced by the expectation, whether justified or not, ofbenefits associated with participation, or of a retaliatory response from seniormembers of a hierarchy in case of refusal to participate.

8. Has contraindications (known allergies, hypersensitivity, or intolerance) to the useof BNT314. A patient with a history of hypersensitivity to any component/excipientsof BNT314 is also excluded.

9. Are pregnant or breastfeeding and cannot discontinue breastfeeding for the durationof the study and for 4 months after receiving the last dose of BNT314.