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

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Solid Tumor; Extensive-stage Small Cell Lung Cancer
• Intervention / Treatment: Drug: BNT411; Drug: Atezolizumab; Drug: Carboplatin; Drug: Etoposide

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: BioNTech clinical trials patient information; Phone Number: +49 6131 9084; Email: patients@biontech.de

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg-Eppendorf - (Recruiting only for part 1B and part 2)
  • Koeln, Germany, 50937
    • Universitaetsklinikum Koeln - (Recruiting only for part 1B and part 2)
  • Mainz, Germany, 55131
    • Universitaetsmedizin der Johannes Gutenberg Universitat Mainz KoeR - (Recruiting only for part 1B and part 2)
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28022
    • Clinica Universidad de Navarra
  • Madrid, Spain, 28050
    • START Madrid - CIOCC. Grupo Hospital de Madrid (HM) - Centro Integral Oncologico Clara Campal (CIOCC)
  • Valencia, Spain, 46026
    • Hospital Universitario La Fe de Valencia
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Edinburgh Cancer Research Centre
  • London, United Kingdom, W1G 6AD
    • Sarah Cannon Research Institute
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Medical Faculty Foundation
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Prisma Health-Upstate Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  1. International normalized ratio (INR) or prothrombin time ≤1.5 x upper limit normal (ULN; unless on therapeutic anticoagulants with values within therapeutic window),
  2. 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:

  1. White blood cell count (WBC) ≥3 x 10^9/L,
  2. 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),
  3. Platelet count ≥100 x 10^9/L,
  4. Hemoglobin (Hgb) ≥9.0 g/dL.

• Adequate hepatic function at screening as determined by:

  1. Total bilirubin ≤1.5 mg/dL (or ≤2.0 mg/dL for patients with known Gilbert's syndrome),
  2. 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:

  1. had radiotherapy, surgery or stereotactic surgery for the brain or leptomeningeal metastases,
  2. have no neurological symptoms (excluding Grade ≤2 neuropathy),
  3. 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,

  4. 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:

  1. ongoing or active infection requiring antibiotic/antiviral/antifungal therapy,
  2. concurrent congestive heart failure (New York Heart Association [NYHA] Functional Classification Class III or IV),
  3. concurrent unstable angina,
  4. concurrent cardiac arrhythmia requiring treatment (excluding asymptomatic atrial fibrillation),
  5. acute coronary syndrome within the previous 6 months,
  6. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 2 only: immune Objective Response Rate (iORR)	iORR defined as the proportion of patients in whom an immune complete response (iCR) or immune partial response (iPR) is observed as best overall response; according to immune RECIST (iRECIST)	up to 2 Years
Part 2 only: immune Disease Control Rate (iDCR)	iDCR defined as the proportion of patients in whom an iCR or iPR or immune stable disease (iSD) (assessed at least 6 weeks after first dose) is observed as best overall response; according to iRECIST	up to 2 Years
Part 2 only: immune Duration of Response (iDOR)	iDOR defined as the time from first objective response (iCR or iPR) to the date of the first occurrence of objective tumor progression (immune confirmed progressive disease; iCPD); according to iRECIST	up to 2 Years
Part 2 only: Progression Free Survival (PFS) time	PFS defined as the time from first dose of BNT411 to first occurrence of objective tumor progression (per RECIST 1.1), or death from any cause, whichever occurs first	up to 3 Years
Part 2 only: Overall Survival (OS) time	OS defined as the time from first dose of BNT411 to death from any cause	up to 3 Years

Collaborators and Investigators

• Sponsor: BioNTech SE
• Investigators: Study Director: BioNTech Responsible Person, BioNTech SE

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2020
• Primary Completion (Actual): January 19, 2024
• Study Completion (Estimated): July 1, 2024

Study Registration Dates

• First Submitted: September 20, 2019
• First Submitted That Met QC Criteria: September 23, 2019
• First Posted (Actual): September 24, 2019

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Solid Tumor; Extensive-stage Small Cell Lung Cancer
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Carboplatin; Etoposide; Atezolizumab
• Other Study ID Numbers: BNT411-01; 2019-003593-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No