IRB Study Number 25-349
Status Recruiting
Locations Fairview Hospital, Cleveland Clinic Main Campus, Hillcrest Hospital, Mercy Hospital, Akron General
Institute Taussig Cancer Institute
Description
Primary Objective:
- To assess the efficacy of BNT327 in combination with chemotherapy (etoposide plus carboplatin) followed by any subsequent therapy compared to atezolizumab in combination with chemotherapy (etoposide plus carboplatin) followed by any subsequent therapy in terms of a hazard ratio for OS in the ITT Set.
Secondary Objectives:
- To evaluate the PFS of BNT327 in combination with chemotherapy (etoposide plus carboplatin) compared to atezolizumab in combination with chemotherapy (etoposide plus carboplatin) in the ITT Set as measured by PFS according to RECIST v1.1 assessed by investigator.
- To evaluate the antitumor activity of BNT327 in combination with chemotherapy (etoposide plus carboplatin) compared to atezolizumab in combination with chemotherapy (etoposide plus carboplatin) in the ITT Set as measured by ORR and DOR.
- To evaluate the PFS rate and OS rate at fixed timepoints in each treatment arm for the ITT Set.
- To evaluate the safety and tolerability of BNT327 in combination with chemotherapy (etoposide plus carboplatin) in the Safety Analysis Set.
- To evaluate PRO scores of quality-of-life using the EORTC QLQ-C30, QLQ-LC29, and FACT-GP5 for the ITT Set.
Exploratory Objectives:
- To evaluate the antitumor activity of BNT327 in combination with chemotherapy (etoposide plus carboplatin) compared to atezolizumab in combination with chemotherapy (etoposide plus carboplatin) in the ITT Set as measured by DCR.
- To assess the PK of BNT327.
- To assess the immunogenicity of BNT327.
- To evaluate predictive, prognostic, and/or pharmacodynamic biomarkers and their correlation with the response to the IMP, and dose as well as the mechanisms of resistance.
- To assess the correlation of exposure to BNT327 and the immunogenicity, efficacy, and TEAEs.
- To evaluate PRO scores of quality-of-life using the EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-LC29, and NSCLC-SAQ for the ITT Set.
Inclusion Criteria
- Are able to give informed consent and have given written consent in accordance with ICH GCP and local legislation prior to the start of any trial-specific procedures.
- 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.
- Are aged ≥18 years at the time of giving informed consent. Local country laws will be followed if the adult age is older than 18 years of age.
- Have histologically or cytologically confirmed ES-SCLC [using the AJCC (American Joint Committee on Cancer) tumor node metastasis staging system combined with Veterans Administration Lung Study Group (VALG)’s two stage classification scheme]. For AJCC tumor node metastasis 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.
- Have not had 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 after the last chemotherapy, radiotherapy, or chemoradiotherapy before diagnosis of ES-SCLC to be eligible.
- Have at least one measurable lesion as the targeted lesion based on RECIST v1.1. 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).
- ECOG performance status of 0 or 1.
- Have a minimum life expectancy of >3 months.
- Have a body weight of ≥40 kg.
- Adequate hematologic and organ function, as defined below:
a. Hematology:
i. 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.
ii. Platelet count ≥100 × 109/L.
iii. 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 2 weeks.
b. Liver function:
i. Bilirubin
-Total bilirubin ≤1.5 × 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.
ii. Alanine aminotransferase and aspartate aminotransferase
-Participants without liver metastasis: ≤2.5 × ULN.
-Participants with liver metastasis: ≤5 × ULN.
iii. Albumin ≥2.5 g/dL.
c. Renal function: 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).
d. 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 <1 g, participant can be enrolled.
e. 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 INR or prothrombin or activated partial thromboplastin is within therapeutic range of intended use of anticoagulant. - Are POCBP who have a negative serum beta-human chorionic gonadotropin test at screening within 7 days of the first 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; permanent sterilized will not be considered permanent sterilization methods are defined in section 10.5.1 will not be considered POCBP and therefore will not be required to undergo pregnancy testing.
- Are POCBP who agree to practice a highly effective form of contraception starting at the Screening Visit and continuously until 6 months after receiving the last dose of IMP. For guidance on highly effective forms of contraception, see Section 10.5.2).
- Men who are sexually active with a partner born female and have not had a vasectomy who agree to use condoms and to ask their sexual partners, to practice a highly effective form of contraception during the trial, starting at the Screening Visit and continuously until 6 months after receiving the last dose of IMP.
For guidance on highly effective forms of contraception, see Section 10.5.2. - Agree not to donate and/or cryopreserve germ cells (sperm, oocytes, ova) for the purposes of assisted reproduction during trial, starting at screening and continuously until 6 months after the last dose of IMP.
Exclusion Criteria
Are pregnant or breastfeeding or are planning pregnancy or to father children during the trial 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 trial, 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 trial treatment:
a. Within 2 weeks: small molecule agents with half-life of <7 days; radiation outside the thoracic cavity including whole brain radiation. Of note, other local radiation for brain lesions (not whole brain) is allowed (see exclusion #7 for further details); local radiation for bone lesions is allowed. Palliative bone radiation or brain stereotactic radiosurgery would not require a washout period, but participants should recover from radiotherapy-related toxicity.
b. 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.
c. Have received prior treatment with anti-VEGF monoclonal antibody, or PD(L)-1/VEGF bispecific antibody.
d. Have received systemic corticosteroids (at a dosage greater than 10 mg/Day of prednisone or an equivalent dose of other corticosteroids) within 7 days prior to the initiation of trial treatment. Note: 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) are allowed.
e. Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior to initiation of the trial treatment.
f. Use of any investigational product within 3 weeks before initiation of trial treatment in this trial or ongoing participation in the active treatment phase of another interventional clinical trial.Have undergone major organ surgery (core needle biopsies are allowed >7 days prior to trial start), significant trauma, or invasive dental procedures (such as dental implants) within 21 days prior to the trial treatment or plan to undergo elective surgery 21 days after the last BNT327 dose. Placement of vascular infusion devices is allowed.
Have received allogeneic hematopoietic stem cell transplantation or organ transplantation.
Have the following central nervous system metastases:
a. Participants with untreated brain metastases that are symptomatic or large (e.g., greater than 2 cm).
b. Participants with treated CNS metastases who are not neurologically stable or on steroids (at a dosage greater than 10 mg/Day of prednisone or an equivalent dose of other corticosteroids) within 7 days before initiating IMP of this trial.
c. 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 diseases such as autoimmune thyroid disease or Type 1 diabetes or skin disorders including psoriasis, vitiligo or alopecia.
Have had other malignant tumors within 3 years prior to the trial treatment. 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 trial treatment:
a. Acute coronary syndrome, coronary artery bypass grafting, congestive heart failure, aortic dissection, stroke, arterial thrombosis, or other Grade 3 and above cardiovascular and cerebrovascular events.
b. 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.Have any of the following hypertension or diabetic conditions prior to trial treatment:
a. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg) while on antihypertensive medicine within 7 days prior to the first dose of trial treatment.
b. Those with a history of hypertensive crisis or hypertensive encephalopathy.
c. Poorly controlled diabetes (as determined by either fasting blood glucose ≥13.3 mmol/L [240 mg/dL] or HbA1C [≥8.5%]) within 7 days prior to the first dose of trial treatment.Have a serious or non-healing wound, or (incompletely healed) bone fracture. This includes history of abdominal fistula, tracheoesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess for which an interval of 6 months must pass before trial entry. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.
Have a significant risk of hemorrhage (per investigator clinical judgment) indicated by any of the following criteria:
a. Tumors with clear radiographic evidence of major blood vessel invasion, as demonstrated by any of the following radiological features: luminal irregularity, discontinuity, distortion or truncation, intraluminal mass formation or any other abnormal imaging finding assessed by the investigator to indicate a risk of bleeding.
b. Tumor lesions with clear invasion of major airways (such as tracheal invasion) or vital organs (such as the heart, pericardium, and esophagus).
c. At least one major cavitation posing hemorrhage risk.
d. Clinically significant hemoptysis defined as coughing up or expelling ≥1 teaspoon/5 mL of blood or small blood clots 4 weeks prior to randomization. Note: Participants with blood in the sputum are allowed to be enrolled.
e. Intracranial or intraspinal hemorrhage within 3 months prior to randomization.
f. Gastrointestinal bleeding within 3 months prior to the first dose of trial treatment.
g. Vascular diseases (such as aortic aneurysm) with a risk of rupture within 3 months prior to randomization.
h. Therapeutic anticoagulation or antiplatelet therapy within 10 days before randomization. Prophylactic use of anticoagulants (such as the use of low molecular weight heparin to maintain venous patency) or antiplatelet medications such as low dose aspirin (≤100 mg/day) is allowed.Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). 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.
Have a history of serious Grade 3 or higher irAEs that led to treatment discontinuation of a prior immunotherapy. Participants with a history of Grade 3 or higher irAEs that did not lead to treatment discontinuation of a prior immunotherapy may be enrolled at the investigator’s discretion.
Have a known or suspected hypersensitivity to the trial treatments including any active ingredient or excipients thereof.
Have known human immunodeficiency virus infection or known acquired immunodeficiency syndrome, with the following exceptions:
a. Participants with CD4+ T-cell counts ≥350 cells/mL per local laboratory should generally be eligible for the trial.
b. Participants who have not had an opportunistic infection within the past 12 months.Participants with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen test result at screening). However, participants with past hepatitis B virus infection or resolved hepatitis B virus infection (defined as the presence of hepatitis B core antibody and absence of hepatitis B surface antigen) are eligible only if they are negative for hepatitis B virus DNA (per local laboratory).
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 AEs from prior antitumor therapy whose AE(s) have not returned to Grade 1 (graded by CTCAE 5.0 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.
Have superior vena cava syndrome or symptoms of spinal cord compression that requires urgent medical intervention.
Have 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 or have active syphilis infection.
Have underlying condition may increase risk of the combination treatment or complicate the interpretation of AEs, as judged by the investigator, or other scenarios that the investigators consider the participant is not eligible for the trial.
Are vulnerable individuals as per ICH E6 definition, 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. This includes all sponsor, trial site, or third party (e.g., CRO, vendor) personnel directly involved in the conduct of the trial and their family members or dependents, as well as all trial site personnel otherwise supervised by the investigator.
