BNT327-01

Inclusion criteria for participation into this trial for Cohort 1 and Cohort 2 are as follows (Note: participants will be assigned to either cohort based on their eligibility):

Cohort 1:

1 Have histologically or cytologically confirmed ES-SCLC [using the AJCC (American Joint Committee on Cancer) TNM (tumor node metastasis) staging system combined with Veterans Administration Lung Study Group (VALG)’s 2 stage classification scheme]. For AJCC TNM staging system: AJCC 8th edition stage IV (T any, N any, M1a/b/c), or T3~4 for multiple lung nodules or tumor/nodule volume that cannot be encompassed in a tolerable radiotherapy plan.

2 Participants without prior systemic therapy for ES-SCLC. However, participants with prior chemoradiotherapy for LS-SCLC must have been treated with curative intent and had a treatment-free interval of at least 6 months since the last systemic anticancer treatment including chemotherapy, radiotherapy, or chemoradiotherapy before the diagnosis of ES-SCLC to be eligible.

Cohort 2:

1 Participants with SCLC who have disease progression/relapse after first-line platinum based chemotherapy with or without immunotherapy.

All participants (Cohort 1 and Cohort 2):

Participants are only eligible for enrollment in this trial if all the following criteria and additional inclusion criteria for Cohort 1 and Cohort 2 apply (at the time of screening):

1 Have given informed consent by signing and dating the informed consent form (ICF) before initiation of any trial-specific procedures.

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

3 Are willing and able to comply with scheduled visits, treatment schedule, the planned trial assessments, laboratory tests, lifestyle restrictions, and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.

4 Have at least one measurable lesion as the targeted lesion based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Lesions treated after prior local treatment (radiotherapy, ablation, interventional procedures, etc.) are generally not considered as target lesions. If the lesion with prior local treatment is the only targeted lesion, evidence based radiology must be provided to demonstrate disease progression (the single bone metastasis or the single central nervous system metastasis should not be considered as a measurable lesion).

5 ECOG performance status of 0 or 1.

6 Have a minimum life expectancy of >3 months.

7 Have adequate organ function, as defined below:

• Hematology:

o Absolute neutrophil count ≥1.5 × 109/L.

Note: Participants may not use granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor to achieve these absolute neutrophil count levels in the past 7 days.

o Platelet count ≥100 × 109/L.

o Hemoglobin ≥90 g/L or 5.6 mmol/L.

Note: Criterion must be met without packed red blood cell transfusion or without erythropoietin dependency within the prior two weeks.

• Liver function:

o Bilirubin

- 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 past medical history.

o Alanine aminotransferase and aspartate aminotransferase

- Participants without liver metastasis: ≤2 × ULN.

- Participants with liver metastasis: ≤5 × ULN.

o Albumin ≥3.0 g/dL.

• Renal function:

o Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min. Cockcroft Gault formula: [(140 – age) × weight (kg) × (0.85, for women only)] / [72 × creatinine (mg/dL)] (conversion of creatinine unit: 1 mg/dL = 88.4 µmol/L).

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

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

8 Are women of childbearing potential (WOCBP) who have a negative serum beta human chorionic gonadotropin test at screening and before each IMP dose. Women born female that are postmenopausal (defined as 12 months with no menses without an alternative medical cause) or permanently sterilized (verified by medical records) will not be considered WOCBP and therefore will not be required to undergo pregnancy testing.

9 Are WOCBP who agree to practice a highly effective form of contraception (for guidance on highly effective forms of contraception, see Section 10.5.2) and to require their male partners to use condoms starting at Screening Visit and continuously until 6 months after receiving the last dose of IMP.

10 Are men who are sexually active with a partner born female and have not had a vasectomy who agree to use condoms and to practice a highly effective form of contraception (for guidance on highly effective forms of contraception, see Section 10.5.2) during the trial, starting at Screening Visit and continuously until 6 months after receiving the last dose of IMP.

11 Are WOCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting at Screening Visit and continuously 6 months after receiving the last dose of IMP.

12 Are men who are willing to refrain from sperm donation, starting at Screening Visit and continuously until 6 months after the last dose of IMP. 

Participants are not eligible for enrollment in this trial if any of the following criteria apply (at the time of screening):

1 Have experienced a previous AE attributed to PD-1 or PD-L1 directed therapy that led to drug discontinuation.

2 Are pregnant or breastfeeding or are planning pregnancy or planning to father children during the trial or within 60 days or five half-lives if known (whichever is longer) after the last dose of IMP.

3 Have a medical, psychological, or social condition which, in the opinion of the investigator, could compromise their wellbeing if they participate in the trial, or that could prevent, limit, or confound the protocol-specified assessments or procedures, or that could impact adherence to protocol described requirements.

4 Have histories of alcoholic abuse, psychotropic drug abuse, or illicit drug addiction.

5 Have histologically or cytologically confirmed SCLC with combined histologies.

6 Have received any of the following therapies or drugs prior to the initiation of trial treatment:

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

• Received chemotherapy, radiotherapy (excluding local radiotherapy for brain lesions), biological therapy, endocrine therapy, or other antitumor drugs (including investigational drugs not yet marketed) within 3 weeks prior to initiation of the trial treatment or within five half-lives of the treatment drug (whichever is longer).

• Received nitrosoureas or mitomycin C within 6 weeks prior to the initiation of the trial treatment, oral fluoropyrimidine-based chemotherapy or small molecule targeted therapy within 2 weeks prior to initiation of the trial treatment or within five half-lives of the treatment drug (whichever is longer).

• Have received other systemic immunostimulatory agents or immunosuppressive therapies (such as IFN-α, IL-2, or methotrexate) within 4 weeks prior to the initiation of trial treatment or are within five half-lives of the treatment drug (whichever is longer).

Exception: excluding 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 received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 3 weeks prior to the initiation of trial treatment.

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

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

• Use of any investigational product (IP) within five half-lives of the trial IMP or any device within 4 weeks before initiation of trial treatment in this trial or ongoing participation in the active treatment phase of another interventional clinical trial.

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

8 Have received allogeneic hematopoietic stem cell transplantation or organ transplantation.

9 Have brain metastases and meet the following criteria (prophylactic cranial irradiation is allowed, if the participant is stable more than 2 weeks before randomization):

• Presence of metastases in the midbrain, pons, medulla oblongata, spinal cord, meninges, or spinal membranes.

• Metastases in the cerebrum or cerebellum (as shown in imaging scans as brain edema and/or progressive tumor growth).

• Presence of cerebral and cerebellar metastases is allowed if the following conditions are met:

o Asymptomatic and no treatment is needed.

o Stable for more than 2 weeks after completion of radiotherapy, if received radiotherapy before enrollment.

o The last corticosteroids or antiepileptic drug treatment was more than 2 weeks prior to the initiation of the trial treatment.

10 Have active autoimmune disease or history of autoimmune diseases with anticipated relapse (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.) are not allowed, except for those with clinically stable autoimmune thyroid disease or type 1 diabetes.

11 Have had other malignant tumors within 5 years prior to the trial treatment are not allowed. Except for those: who had local treatment and have been cured (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; including prostate cancer with CR within the past 3 years).

12 Have any of the following heart conditions within 6 months prior to the trial 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 (QTcF) >480 ms.

• Use of cardiac pacemaker.

• Cardiac troponin I or N >2 x ULN.

13 Have any of the following hypertension or diabetic conditions prior to initiation of trial treatment:

• Poorly controlled diabetes (fasting blood glucose ≥13.3 mmol/L).

• Uncontrolled hypertension (systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg) while on antihypertensive medicine.

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

14 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 trial. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.

15 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 thrombosis or embolism, or significant vascular disease (such as aortic aneurysm requiring surgery) within 6 months prior to the trial treatment.

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

• Had anticoagulant therapy for therapeutic purposes (except low molecular weight heparin) within 14 days prior to the initiation of trial treatment.

• Received antiplatelet drugs including, but not limited to, aspirin (>100 mg/day), clopidogrel (>75 mg/day), dipyridamole, ticlopidine, cilostazol or any herbal or folk medicines know to be associated with increased bleeding risks, within 10 days prior to the initiation of trial treatment.

16 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.

17 Have uncontrolled tumor-related pain requiring analgesic treatment not managed by a stable analgesic regimen. For asymptomatic metastatic lesion, if its growth may cause dysfunction or intractable pain (e.g., epidural metastasis without spinal cord compression), local treatment should be considered before screening as indicated.

18 Participants with a history of Grade 4 or higher immune-related AEs (irAEs) that led to treatment discontinuation of a prior checkpoint inhibitor should be discussed with the sponsor.

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

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

• Participants with CD4+ T cell (CD4+) counts ≥350 cells/mL per local laboratory should generally be eligible for the trial.

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

21 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.

22 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.

23 Are subject to exclusion periods from another investigational trial.

24 Are vulnerable individuals, i.e., are individuals whose willingness to volunteer in a clinical trial 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.

25 Participants with AEs from prior antitumor therapy whose AE(s) have not returned to Grade 1 (graded by Common Terminology Criteria for Adverse Events version 5.0 [CTCAE v5.0] criteria) or below (unless the investigator determines that certain AEs pose no safety risk to participants, such as hair loss, Grade 2 peripheral neuropathy or stable hypothyroidism under hormone replacement therapy) are not eligible for the trial.

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

27 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.

28 Have active tuberculosis or history of tuberculosis that was not successfully treated.

29 Have underlying condition(s) that may increase the risk of the combination treatment or complicate the interpretation of AEs, as judged by the investigator, or other scenarios in which the investigator consider the participant as not eligible for the trial.

30 Those who are expected to require non-trial antitumor drug therapy during the trial. 

Research Nurse: Lizzie Coates (x2031) Elizabeth.Coates@LTHTR.nhs.uk