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

NCT04101357 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: BNT411-012019-003593-17
• Study Type: interventional
• Target: 54
• Locations: 4 countries
• Sites: 12

Brief Summary

This first-in-human (FIH) trial aimed 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.

Conditions

Solid Tumor; Extensive-stage Small Cell Lung Cancer

Keywords

Solid Tumor; Extensive-stage Small Cell Lung Cancer

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Dose Limiting Toxicities (DLTs)

  DLTs were defined as any non-immune-related adverse events (AEs) or immune-related AEs during the first treatment cycle that was of Grade 3 and that did not resolve to Grade 1 or lower within a week, or that were of Grade 4. AEs were graded for severity using National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0), where Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4 - Life-threatening consequences; and Grade 5: Death related to AE.

  Cycle 1 (21 Days)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs (TESAEs) and Grade >=3 TEAEs

  A TEAE was defined as any AE with an onset date on or after the first administration of trial treatment (if AE was absent before the first administration of trial treatment) or worsened after the first administration of trial treatment (if AE was present before the first administration of trial treatment). AEs occurring more than 60 days after last treatment administration were considered as treatment-emergent only if assessed as related to the trial treatment by the investigator. Serious adverse event (SAE): any untoward medical occurrence that, at any dose: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect or was another medically important condition. AE were graded for severity using NCI-CTCAE v5.0, where Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4 - Life-threatening consequences; and Grade 5: Death related to AE.

  From Baseline until 60 days after last dose of study treatment (3 years and 11 months)

• Number of Participants Reporting Dose Reduction and/or Discontinuation of BNT411 Due to TEAEs

  Participants with dose reduction and/or discontinuation of BNT411 due to TEAEs are reported.

  From Baseline until 60 days after last dose of study treatment (3 years and 11 months)

• Maximal Tolerated Dose (MTD) of BNT411

  The MTD defined as the highest tolerated dose was reported based on the DLTs and TEAEs experienced by participants.

  Cycle 1 (21 days)

• Recommended Phase 2 Dose (RP2D) of BNT411

  RP2D was based on integrated evaluation of safety, tolerability, clinical benefit, pharmacokinetic (PK), and pharmacodynamic data, for all dose levels was tested.

  Cycle 1 (21 days)

Secondary Outcomes (7)

• Pharmacokinetics (PK) Assessment for BNT411: Area Under the Concentration Time Curve (AUC0-last)

  Part 1A: Cycle 1 Day 1; Cycle 2 Day 1; Part 1B: Cycle 1 Day 2; Cycle 2 Day 2 (each cycle duration=21 days)

• PK Assessment for BNT411: Clearance (CL)

  Part 1A: Cycle 1 Day 1; Cycle 2 Day 1; Part 1B: Cycle 1 Day 2; Cycle 2 Day 2 (each cycle duration=21 days)

• PK Assessment for BNT411: Volume of Distribution (Vd)

  Part 1A: Cycle 1 Day 1; Cycle 2 Day 1; Part 1B: Cycle 1 Day 2; Cycle 2 Day 2 (each cycle duration=21 days)

• PK Assessment for BNT411: Maximum Plasma Concentration (Cmax)

  Part 1A: Cycle 1 Day 1; Cycle 2 Day 1; Part 1B: Cycle 1 Day 2; Cycle 2 Day 2 (each cycle duration=21 days)

• PK Assessment for BNT411: Time to Reach Cmax (Tmax)

  Part 1A: Cycle 1 Day 1; Cycle 2 Day 1; Part 1B: Cycle 1 Day 2; Cycle 2 Day 2 (each cycle duration=21 days)

Study Arms (3)

Part 1A - monotherapy dose escalation

EXPERIMENTAL

BNT411 monotherapy

Drug: BNT411

Part 1B - combination dose escalation

EXPERIMENTAL

BNT411 in combination with atezolizumab, carboplatin, and etoposide.

Drug: BNT411; Drug: Atezolizumab; Drug: Carboplatin; Drug: Etoposide

Part 2 - expansion cohorts

EXPERIMENTAL

BNT411 either as monotherapy or in combination with atezolizumab, carboplatin, and etoposide. Please note that the sponsor decided not to continue with this part of this trial.

Drug: BNT411; Drug: Atezolizumab; Drug: Carboplatin; Drug: Etoposide

Interventions

BNT411 DRUG

intravenous

Part 1A - monotherapy dose escalation; Part 1B - combination dose escalation; Part 2 - expansion cohorts

Atezolizumab DRUG

intravenous

Part 1B - combination dose escalation; Part 2 - expansion cohorts

Carboplatin DRUG

intravenous

Part 1B - combination dose escalation; Part 2 - expansion cohorts

Etoposide DRUG

intravenous

Part 1B - combination dose escalation; Part 2 - expansion cohorts

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For Part 1A:
• Histologically confirmed solid tumor (cytology was allowed for non-small cell lung cancer \[NSCLC\], small cell lung cancer \[SCLC\] and pancreatic cancer) that was metastatic or unresectable and for which there was no available standard therapy likely to confer clinical benefit, or patients who were 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) were treatment-free for at least 6 months since last chemo/radiotherapy.
• Did not have interstitial lung disease or active, non-infectious pneumonitis.
• For Both Part 1A and Part 1B:
• Male and female \>= 18 years of age.
• Must have signed an informed consent form (ICF) indicating that he or she understood the purpose of and procedures required for the trial and were 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).

You may not qualify if:

• Prior and Concomitant Therapy:
• Had received prior systemic therapy with a TLR7 agonist.
• Had been receiving: radiotherapy, chemotherapy, or molecularly-targeted agents or tyrosine kinase inhibitors within 2 weeks or 5 half-lives (whichever was 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.
• Received concurrent systemic (oral or intravenous) steroid therapy \>10 mg prednisone daily or its equivalent for an underlying condition.
• Received concurrent strong inhibitors or inducers of the cytochrome P450 enzymes.
• Had major surgery within the 4 weeks before the first dose of BNT411.
• Had 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.
• Had 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 was allowed; alopecia of any grade was allowed.
• Medical Conditions
• Evidence of new or growing brain or leptomeningeal metastases during screening. Patients with known brain or leptomeningeal metastases might have been 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,
• were not undergoing acute corticosteroid therapy or steroid taper.

Sponsors & Collaborators

• BioNTech SE: lead

Study Sites (12)

Cedars-Sinai Medical Center

Los Angeles, California, 90048, United States

Location

Northwestern Medical Faculty Foundation

Chicago, Illinois, 60611, United States

Location

Prisma Health-Upstate Cancer Institute

Greenville, South Carolina, 29605, United States

Location

Universitaetsklinikum Koeln - (Recruiting only for part 1B and part 2)

Cologne, 50937, Germany

Location

University Medical Center Hamburg-Eppendorf - (Recruiting only for part 1B and part 2)

Hamburg, 20246, Germany

Location

Universitaetsmedizin der Johannes Gutenberg Universitat Mainz KoeR - (Recruiting only for part 1B and part 2)

Mainz, 55131, Germany

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Clinica Universidad de Navarra

Madrid, 28022, Spain

Location

START Madrid - CIOCC. Grupo Hospital de Madrid (HM) - Centro Integral Oncologico Clara Campal (CIOCC)

Madrid, 28050, Spain

Location

Hospital Universitario La Fe de Valencia

Valencia, 46026, Spain

Location

Edinburgh Cancer Research Centre

Edinburgh, EH4 2XU, United Kingdom

Location

Sarah Cannon Research Institute

London, W1G 6AD, United Kingdom

Location

MeSH Terms

Conditions

Small Cell Lung Carcinoma

Interventions

atezolizumab; Carboplatin; Etoposide

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates

Limitations and Caveats

The planned Part 2 of the study was not conducted as the trial was terminated prematurely.

Results Point of Contact

• Title: BioNTech clinical trials patient information
• Organization: BioNTech SE

patients@biontech.de

+49 6131 9084

Study Officials

• BioNTech Responsible Person

  BioNTech SE

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 20, 2019
• First Posted: September 24, 2019
• Study Start: June 19, 2020
• Primary Completion: January 19, 2024
• Study Completion: May 23, 2024
• Last Updated: March 18, 2025
• Results First Posted: March 18, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2); US (3); ES (4); DE (3)