Safety, Preliminary Effectiveness of BNT327, an Investigational Therapy for Patients With Small-cell Lung Cancer in Combination With Chemotherapy

Are pregnant or breastfeeding or are planning pregnancy or planning to father children 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 the investigator, could compromise their wellbeing if they participate in the study, or that could prevent, limit, or confound the protocol-specified assessments or procedures, or that could impact adherence to protocol-described requirements.

Have histologically or cytologically confirmed SCLC with combined histologies.

Have received any of the following therapies or drugs within the noted time intervals prior to the initiation of study treatment:

* Within 2 weeks: small molecule targeted agents with half-life of \<7 days; or radiation not involving the thoracic cavity; local radiation for brain lesion is allowed; local radiation for bone lesions is allowed.

* Within 4 weeks: radiation involving the thoracic cavity; small molecule targeted agents with half-life of ≥7 days; monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or T-cell or other cell-based therapies.

* Participants who received prior treatment with a PDL-1/VEGF bispecific antibody.

* Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 10 days prior to the initiation of study treatment. Note: The following are allowed: local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short-term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens).

* Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior to initiation of the study treatment.

* Received broad-spectrum intravenous antibiotics therapy within 2 weeks prior to initiation of study treatment.

* Use of any non-study IMP within 3 weeks before initiation of study treatment in this study or ongoing participation in the active treatment phase of another interventional clinical study.

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

Have received allogeneic hematopoietic stem cell transplantation or organ transplantation.

Have the following central nervous system metastases:

* Participants with untreated brain metastases that are symptomatic or large (e.g., \>2 cm).

* Participants who received treatment for central nervous system metastases are not neurologically stable or still on steroids 10 days before initiating IMP of this study.

* Participants with known leptomeningeal metastases.

Have active autoimmune disease or history of autoimmune diseases with anticipated relapse (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.), except for those with clinically stable autoimmune thyroid disease or type 1 diabetes.

Have had other malignant tumors within 2 years prior to the study treatment are not allowed. Except for those: who have been cured with local treatment (such as basal cell or squamous cell carcinoma of the skin, superficial or non-invasive bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, papillary carcinoma of thyroid and early stage prostate cancer).

Have any of the following heart conditions within 6 months prior to the study treatment:

* Acute coronary syndrome, coronary artery bypass grafting, congestive heart failure, aortic dissection, stroke, or other Grade 3 and above cardiovascular and cerebrovascular events.

* New York Heart Association functional classification ≥II heart failure or left ventricular 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 \>480 ms (the electrocardiogram can be 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 of study treatment:

* Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) while on antihypertensive medicine.

* Those with a history of hypertensive crisis or hypertensive encephalopathy.

* Poorly controlled diabetes (fasting blood glucose ≥13.3 mmol/L \[240 mg/dL\]).

Have serious non-healing wounds, ulcers, or bone fractures. This includes history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess for which an interval of 6 months must pass before enrollment into this study. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.

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

* History of intracranial or intraspinal hemorrhage.

* Tumor lesions invading large vessels and with significant risk of bleeding

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

Have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Participants with indwelling catheters (e.g., PleurX) are allowed. However, participants who are clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis or with indwelling catheters, e.g., PleurX) are allowed.

Participants with a history of serious Grade 3 or higher immune-related adverse events (irAEs) that led to treatment discontinuation of a prior immunotherapy. Participants with a history of Grade ≥3 irAEs that did not lead to discontinuation of a prior immunotherapy but fully recovered may be enrolled per investigator's discretion. The investigator may request sponsor guidance in such cases.

Have a known or suspected hypersensitivity to the study treatments including any active ingredient or excipients thereof.

Have known human immunodeficiency virus infection or known acquired immunodeficiency syndrome, with the following exceptions:

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

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

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

Have an active hepatitis C virus infection; individuals who have completed curative antiviral treatment with hepatitis C virus viral load below the limit of quantification are allowed.

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 of pulmonary fibrosis, or currently diagnosed with severe lung diseases such as interstitial pneumonia, pneumoconiosis, chemical pneumonitis, or any other condition resulting in significant impairment in lung function. Exception: Asymptomatic interstitial changes caused by previous radiation therapy, chemotherapy, or other factors such as smoking are acceptable.

Have active tuberculosis.

Are vulnerable individuals, i.e., are individuals whose willingness to volunteer in a clinical study may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. This includes all sponsor, study site, or third party (e.g., contract research organization, vendor) personnel directly involved in the conduct of the sudy and their family members or dependents, as well as all study site personnel otherwise supervised by the investigator.

What this study is about