IRB Study Number 25-708
Status Recruiting
Phases Phase 1, Phase 2
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Part 1 (Dose Escalation)
To determine the RP2D of BNT324 in combination with BNT327 by assessing the safety and tolerability in participants with advanced lung cancer.
By dose level:
•Occurrence of DLTs during the DLT evaluation period (Cycle 1, 21 days).
•Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs from the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first.
•Occurrence of dose interruption, reduction, and treatment discontinuations due to TEAEs by dose level from the time of the first dose of IMP to 90 days after the last dose of IMP or until new anticancer therapy is started, whichever occurs first.
Part 2 (Dose Optimization/Signal Seeking)
Lead indications Cohort 1 and Cohort 2:
To determine the optimal dose of BNT324 in combination with BNT327 by assessing the safety profile and efficacy of the combination therapy in the randomized dose optimization cohorts in the lead cohorts (Cohort 1 treatment naive non-sq NSCLC and Cohort 2 relapsed/progressive SCLC).
By cohort and treatment arm:
•Occurrence of TEAEs, serious TEAEs, treatment-related TEAEs, and treatment-related serious TEAEs from the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first.
•Occurrence of dose interruption, reduction, and treatment discontinuation due to TEAEs from the time of the first dose of IMP to 90 days after the last IMP dose or until new anticancer therapy is started, whichever occurs first.
•ORR, defined as the proportion of participants in whom a confirmed CR or PR is observed as best overall response (per RECIST 1.1 based on the investigator’s assessment).
Efficacy signal seeking cohorts 3-7:
To evaluate the efficacy of BNT324 in combination with BNT327 according to RECIST 1.1.
By cohort:
•ORR, defined as the proportion of participants in whom a confirmed CR or PR is observed as best overall response (per RECIST 1.1 based on the investigator’s assessment).
Inclusion Criteria
1) Have given informed consent by signing and dating an ICF before initiation of any trial-specific procedures.
2) Are willing and able to comply with scheduled visits, treatment schedule, the planned trial assessments, lifestyle restrictions, and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.
3) Aged ≥18 years at the time of giving informed consent.
4) Histological or cytological confirmed unresectable advanced/metastatic lung cancer. Histological classification may be based on tumor samples prior to metastatic disease. Participants with mixed histology must be classified based on the main component.
Participants with NSCLC are eligible with any or no PD-L1 expression.
Participants with AGA-positive disease must have received targeted therapy prior to enrollment in this trial.
5) Have measurable disease defined by RECIST 1.1 (see Section 8.3.1 for details).
6) All participants (except for participants with SCLC) must provide a tumor tissue sample (FFPE slides) from archival tissue (note: for participants with SCLC, archival tissue should be provided, if possible, but it is not mandatory for enrollment). The archival tissue can be an FFPE block or freshly cut slides derived from the initial diagnosis or recurrent setting within the previous 2 years. If archival tissue is not available, a fresh biopsy must be collected before C1D1. Details are provided in the Laboratory Manual.
7) Have ECOG PS of 0 or 1 (see Section 8.4.4 for details).
8) Have a life expectancy of ≥12 weeks.
9) Have an adequate organ and bone marrow function within 7 days before randomization/enrollment. For all parameters listed below, the most recent results available must be used to meet the inclusion criteria:
Hematology (without receiving erythropoietin [EPO], granulocyte colony-stimulating factor [G-CSF], or granulocyte-macrophage colony-stimulating factor [GM-CSF] within 14 days and blood, red blood cell, platelet transfusion within 7 days prior to the sampling)
9a) Platelet count ≥100,000/mm3
9b) Hemoglobin ≥9.0 g/dL
9c) ANC ≥1,500/mm3
Chemistry
9d) Creatinine Estimated creatinine clearance >45 mL/min/1.73 m2 using the Cockcroft-Gault equation (Cockcroft and Gault, 1976) [(140 – age in years) × weight (kg) × (0.85, for women only)]/ [72 × creatinine (mg/dL)] (conversion of creatinine unit: 1 mg/dL = 88.4 μmol/L) and eGFR
>45 mL/min/1.73 m2 using the 2021 CKD-EPI formula using creatinine with or without cystatin C with no race factor (Inker et al. 2021).
9e) AST and ALT ≤2 × ULN (if liver metastases are present, ≤5 × ULN)
9f) Total bilirubin ≤1.5 × ULN if no liver metastases or <2 × ULN in the presence of Gilbert’s syndrome or liver metastases at baseline
9g) Albumin ≥3.0 g/dL
Coagulation
9h) International normalized ratio / prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤1.5 × ULN, except for participants receiving anticoagulant therapy, who must have international normalized ratio within therapeutic range as deemed appropriate by the investigator
10) Have had an adequate treatment washout period before randomization/enrollment, defined as in the table below:
Previous treatment Washout period
10a) Anticancer hormonal therapy ≥1 week
10b) Chemotherapy ≥3 weeks
10c) Immunotherapy (non-antibody-based therapy) ≥3 weeks
10d) Small molecule targeted agents ≥2 weeks or 5 half-lives of the small molecule targeted agents, whichever is longer. Where a risk of hyper-progression upon discontinuation exists, treatment can be continued until 5 days prior to trial treatment, as long as related toxicities are resolved or meet the trial’s eligibility criteria, except for agents that have been identified as CYP3A4 and CYP2D6 inhibitor.
10e) Antibody-based anticancer
Exclusion Criteria
1) Prior treatment with B7-H3 targeted therapy.
2) Prior treatment with ADC with topoisomerase inhibitor (e.g., datopotamab deruxtecan, trastuzumab deruxtecan). Note: This exclusion applies to participants in the first-line/treatment-naïve cohorts in the advanced/metastatic setting. Prior treatment with ADC with topoisomerase inhibitor payload is only allowed for participants in the second-line cohorts in the advanced/metastatic setting.
3) Is a candidate to locoregional treatment (including surgical resection, stereotactic radiotherapy or tumor ablation) with potential to induce complete or near complete response and prolonged tumor control (sometimes described as “radical” intent), per investigator’s assessment.
4) Has a history of significant hematologic toxicity to prior lines of therapy, as assessed by investigator, e.g., Grade 4 febrile neutropenia or recurrent/persistent Grade 3 to 4 neutropenia.
5) Have an uncontrolled concomitant or intercurrent illness, that in the opinion of the investigator, contra-indicates trial participation, limits compliance with trial procedures or substantially increases the risk of incurring AEs, including:
•bleeding diathesis or active hemorrhage,
•active infection,
•Child-Pugh class B or C cirrhosis,
•pulmonary disease with significant impact in lung function,
•oncologic emergencies or complications (e.g. malignant hypercalcemia, superior vena cava syndrome, carcinoid syndrome that is unstable and with available alternative therapies),
•psychiatric or abuse condition.
6) Have uncontrolled or significant cardiovascular disease or diabetes conditions including any of the following:
•Medical history of unstable angina, acute coronary syndrome, cerebral vascular accident or other Grade ≥3 cardiovascular events, within 6 months before randomization/enrollment or symptomatic chronic heart failure (New York Heart Association Class II to IV). Participants with troponin levels above ULN at screening and without any myocardial infarction related symptoms should have a cardiologic consultation before randomization/enrollment to rule out myocardial infarction.
•Central or symptomatic peripheral pulmonary embolism within 3 months prior to randomization/enrollment. Participants with deep venous thrombosis and incidentally diagnosed peripheral pulmonary embolism are eligible if on a stable antithrombotic regimen.
•Uncontrolled hypertension (defined as systolic BP ≥160 mm Hg and/or diastolic BP ≥100 mm Hg) maintained over time and despite antihypertensive treatment, or participants with a history of hypertensive crisis or hypertensive encephalopathy.
•Uncontrolled and/or clinically important cardiac arrhythmias.
•Fredericia’s formula-QT corrected interval QTcF prolongation to >470 ms based on average of screening 12-lead ECG in triplicate.
•Have LVEF <50% by either ECHO or MUGA within 28 days before randomization/enrollment.
•Poorly controlled diabetes (fasting blood glucose ≥13.3 mmol/L [240 mg/dL]).
7) Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment.
8) Have a history of (non-infectious) ILD/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
Asymptomatic interstitial changes caused by previous radiotherapy, chemotherapy, or other factors such as smoking are acceptable.
9) Have clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the trial if they have recovered from the acute toxic effect of radiotherapy. Participants with untreated, asymptomatic brain metastasis
