Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy Trial of BNT411

Study Overview
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Brief Summary
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This first-in-human (FIH) trial aims to establish a safe dose of BNT411 as a monotherapy and in combination with atezolizumab, carboplatin and etoposide. BNT411 is a toll-like receptor 7 (TLR7) agonist which is expected to mount broad innate and adaptive immune reactions, especially in combination with cytotoxic therapies and immune checkpoint inhibitors.

Detailed Description
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The first part (Part 1A) of this trial is a FIH, open-label, dose-escalation trial studying BNT411 monotherapy in patients with different types of malignant solid tumors in order to determine the safety profile of BNT411. The second part (Part 1B) aims to determine further the safety profile of BNT411 in combination with atezolizumab, carboplatin and etoposide in patients with chemotherapy-naïve ES-SCLC. The third part (Part 2) is the expansion phase to explore BNT411 further as a monotherapy or in combination with atezolizumab, carboplatin and etoposide in select tumor indications. Different treatment schedules and other indications may also be explored in Part 2.

Official Title
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Phase 1/2a, First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of BNT411 as a Monotherapy in Patients With Solid Tumors and in Combination With Atezolizumab, Carboplatin and Etoposide in Patients With Chemotherapy-naïve Extensive-stage Small Cell Lung Cancer (ES-SCLC)

Conditions
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Solid Tumor, Extensive-stage Small Cell Lung Cancer

Intervention / Treatment
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* Drug: BNT411
* Drug: Atezolizumab
* Drug: Carboplatin
* Drug: Etoposide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Part 1A: Histologically confirmed solid tumor (cytology is allowed for non-small cell lung cancer [NSCLC], small cell lung cancer [SCLC] and pancreatic cancer) that is metastatic or unresectable and for which there is no available standard therapy likely to confer clinical benefit, or patients who are not candidates for such available therapy. For Part 1B: Histologically or cytologically confirmed ES-SCLC (per the Veterans Administration Lung Study Group [VALG] staging system) who received no prior chemotherapy for extensive stage disease. Those treated with prior chemo/radiotherapy with curative intent for limited-stage small cell lung cancer (LS-SCLC) should be treatment-free for at least 6 months since last chemo/radiotherapy. No interstitial lung disease or active, non-infectious pneumonitis. For Both Part 1A and Part 1B: Male and female ≥18 years of age. Must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the trial and are willing to participate in the trial prior to any trial-related assessments or procedures. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Measurable disease according to RECIST 1.1. Albumin level at screening ≥30 g/L. Adequate coagulation function at screening as determined by: International normalized ratio (INR) or prothrombin time ≤1.5 x upper limit normal (ULN; unless on therapeutic anticoagulants with values within therapeutic window), Activated partial thromboplastin time (aPTT) ≤1.5 x ULN (unless on therapeutic anticoagulants with values within therapeutic window). Adequate hematologic function at screening as determined by: White blood cell count (WBC) ≥3 x 10^9/L, Absolute neutrophil count (ANC) ≥1.5 x 10^9/L (patient may not use granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) to achieve these WBC and ANC levels), Platelet count ≥100 x 10^9/L, Hemoglobin (Hgb) ≥9.0 g/dL. Adequate hepatic function at screening as determined by: Total bilirubin ≤1.5 mg/dL (or ≤2.0 mg/dL for patients with known Gilbert's syndrome), Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN; or ≤5 x ULN in patients with metastatic liver disease. Adequate renal function at screening as determined by: a. Glomerular filtration rate (GFR) ≥60 mL/min/1.73 m^2 - e.g., according to the abbreviated Modification of Diet in Renal Disease (MDRD) equation: GFR = 186 × (SCr^-1.154) × (age^-0.203) (where SCr, the serum creatinine level, is expressed in mg/dL; multiplied by 0.742 if the patient is female; multiplied by 1.212, if the patient is African-American (Levey et al., 1999). Able to attend trial visits as required by the protocol. Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) test/value at screening. Patients who are postmenopausal or permanently sterilized can be considered as not having reproductive potential. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial, until 6 months after last BNT411 treatment. A man who is sexually active with a WOCBP and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the trial and for 6 months after receiving the last dose of BNT411. All patients must provide an Formalin Fixed Paraffin Embedded (FFPE) sample from the latest available archival tumor tissue. If such tissue cannot be provided, the sponsor's approval of enrollment is needed. Exclusion Criteria: Prior and Concomitant Therapy: Has received prior systemic therapy with a TLR7 agonist. Has been receiving: radiotherapy, chemotherapy, or molecularly-targeted agents or tyrosine kinase inhibitors within 2 weeks or 5 half-lives (whichever is longer) of the start of trial treatment; immunotherapy/monoclonal antibodies within 3 weeks of the start of trial treatment; any live vaccine within 4 weeks of the start of trial treatment; nitrosoureas, antibody-drug conjugates, or radioactive isotopes within 6 weeks of the start of trial treatment. Receives concurrent systemic (oral or intravenous) steroid therapy >10 mg prednisone daily or its equivalent for an underlying condition. Receives concurrent strong inhibitors or inducers of the cytochrome P450 enzymes. Has had major surgery within the 4 weeks before the first dose of BNT411. Has ongoing or active infection requiring intravenous treatment with anti-infective therapy that has been administered less than two weeks prior to first dose of trial treatment. Has side effects of any prior therapy or procedures for any medical condition not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.5 Grade ≤1. Notes: peripheral neuropathy Grade ≤2 is allowed; alopecia of any grade is allowed. Medical Conditions Current evidence of new or growing brain or leptomeningeal metastases during screening. Patients with known brain or leptomeningeal metastases may be eligible if they: had radiotherapy, surgery or stereotactic surgery for the brain or leptomeningeal metastases, have no neurological symptoms (excluding Grade ≤2 neuropathy), have stable brain or leptomeningeal disease on the computed tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the informed consent, are not undergoing acute corticosteroid therapy or steroid taper. Notes: Patients with central nervous system symptoms should undergo a CT scan or MRI of the brain to exclude new or progressive brain metastases. Spinal bone metastases are allowed, unless imminent fracture with cord compression is anticipated. Has history of seizures other than isolated febrile seizure in childhood; has a history of a cerebrovascular accident or transient ischemic attack less than 6 months ago. Has effusions (pleural, pericardial, or ascites) requiring drainage. Has eye pathology likely to confound observation of potential ocular adverse events. Has a fever ≥38°C within 3 days before signing the ICF. Has a history of autoimmune disease active or past including but not limited to inflammatory bowel disease, systemic lupus erythematosus (SLE), ankylosing spondylitis, scleroderma, or multiple sclerosis. Has any active immunologic disorder requiring immunosuppression with steroids or other immunosuppressive agents (e.g., azathioprine, cyclosporine A) with the exception of patients with isolated vitiligo, resolved childhood asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism, and euthyroid patients with a history of Grave's disease. Patients with controlled hyperthyroidism must be negative for thyroglobulin, thyroid peroxidase antibodies, and thyroid-stimulating immunoglobulin prior to trial drug administration. Known history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-cell (CD4+) counts <350 cells/µL and with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections. Known history/positive serology for hepatitis B requiring active anti-viral therapy (unless immune due to vaccination or resolved natural infection or unless passive immunization due to immunoglobulin therapy). Patients with positive serology must have Hepatitis B virus (HBV) viral load below the limit of quantification. Active Hepatitis C virus (HCV) infection; patients who have completed curative antiviral treatment with HCV viral load below the limit of quantification are allowed. Notes: Country-specific criteria for Germany - To confirm that a patient would be eligible, an active infection with HIV/Hepatitis B or C should be ruled out by serum blood test at screening. Has a known hypersensitivity to a component of BNT411 drug product, or another similar compound. Has another primary malignancy that has not been in remission for at least 2 years, with the exception of those with a negligible risk of metastasis or death (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ). Other Comorbidities Has abnormal electrocardiograms (ECGs) that are clinically significant, such as Framingham-corrected QT interval >480 ms. In the opinion of the treating investigator, has any concurrent conditions that could pose an undue medical hazard or interfere with the interpretation of the trial results; these conditions include, but are not limited to: ongoing or active infection requiring antibiotic/antiviral/antifungal therapy, concurrent congestive heart failure (New York Heart Association [NYHA] Functional Classification Class III or IV), concurrent unstable angina, concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation), acute coronary syndrome within the previous 6 months, significant pulmonary disease (shortness of breath at rest or on mild exertion) for example due concurrent severe obstructive pulmonary disease. Has a cognitive, psychological or psychosocial impediment that would impair the ability of the patient to receive therapy according to the protocol or adversely affect the ability of the patient to comply with the informed consent process, protocol, or protocol-required visits and procedures. Is pregnant or breastfeeding. Has any contraindication to atezolizumab, carboplatin or etoposide as per US prescribing information (USPI) or summary of product characteristics (SmPC) in Part 1B.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A - monotherapy dose escalation<br>BNT411 monotherapy | Drug: BNT411<br>* intravenous<br>|
| Experimental: Part 1B - combination dose escalation<br>BNT411 in combination with atezolizumab, carboplatin, and etoposide | Drug: BNT411<br>* intravenous<br>Drug: Atezolizumab<br>* intravenous<br>Drug: Carboplatin<br>* intravenous<br>Drug: Etoposide<br>* intravenous<br>|
| Experimental: Part 2 - expansion cohorts<br>BNT411 either as monotherapy or in combination with with atezolizumab, carboplatin, and etoposide | Drug: BNT411<br>* intravenous<br>Drug: Atezolizumab<br>* intravenous<br>Drug: Carboplatin<br>* intravenous<br>Drug: Etoposide<br>* intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Incidence of dose-limiting toxicities (DLTs) | Occurrence of DLTs within a patient during the DLT evaluation period | 21 Days after the first dose | 
| Part 1 and 2: Incidence of TEAEs | Occurrence of treatment-emergent adverse events (TEAE) within a patient including Grade ≥3, serious, fatal TEAE by relationship | up to 2 Years | 
| Part 1 and 2: Incidence of investigational medicinal product (IMP) dose reductions | Occurrence of dose reduction of BNT411 within a patient due to TEAEs | up to 2 Years | 
| Part 1 and 2: Incidence of IMP treatment discontinuations due to toxicity | Occurrence of discontinuation of BNT411 within a patient due to TEAEs | up to 2 Years | 
| Part 1 only: Determination of maximal tolerated dose (MTD) | MTD defined as the highest tolerated dose | Up to 2 Years | 
| Part 1 only: Determination of the recommended Phase 2 dose (RP2D) | RP2D based on integrated evaluation of safety, tolerability, clinical benefit, pharmacokinetic (PK), and pharmacodynamic data, for all dose levels tested | Up to 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: PK assessments: Area under the concentration time curve (AUC) |  | up to 2 Years | 
| Part 1 and 2: PK assessments: Clearance (CL) |  | up to 2 Years | 
| Part 1 and 2: PK assessments: Volume of distribution (VD) |  | up to 2 Years | 
| Part 1 and 2: PK assessments: Maximum Plasma Concentration (Cmax) |  | up to 2 Years | 
| Part 1 and 2: PK assessments: Time to Cmax (Tmax) |  | up to 2 Years | 
| Part 1 and 2: PK assessments: Trough concentration (Ctrough) |  | up to 2 Years | 
| Part 1 and 2: PK assessments: Terminal half-life (T1/2) |  | up to 2 Years | 
| Part 2 only: Objective Response Rate (ORR) | ORR defined as the proportion of patients in whom a complete response (CR) or partial response (PR) is observed as best overall response; according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | up to 2 Years | 
| Part 2 only: Disease Control Rate (DCR) | DCR defined as the proportion of patients in whom a CR or PR or stable disease (SD) (assessed at least 6 weeks after first dose) is observed as best overall response; according to RECIST 1.1 | up to 2 Years | 
| Part 2 only: Duration of Response (DOR) | DOR defined as the time from first objective response (CR or PR) to the date of the first occurrence of objective tumor progression (progressive disease; PD) or death from any cause, whichever occurs first; according to RECIST 1.1 | up to 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid Tumor, Extensive-stage Small Cell Lung Cancer