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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04101357
Recruitment Status : Recruiting
First Posted : September 24, 2019
Last Update Posted : July 28, 2020
Sponsor:
Information provided by (Responsible Party):
BioNTech SE ( BioNTech Small Molecules GmbH )

Tracking Information
First Submitted Date  ICMJE September 20, 2019
First Posted Date  ICMJE September 24, 2019
Last Update Posted Date July 28, 2020
Actual Study Start Date  ICMJE June 19, 2020
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2019)
  • Incidence of DLTs [ Time Frame: 21 Days ]
    Occurrence of DLTs within a patient during the DLT evaluation period
  • Incidence of TEAEs [ Time Frame: up to 2 Years ]
    Occurrence of treatment-emergent adverse events (TEAE) within a patient
  • Incidence of IMP dose reductions [ Time Frame: up to 2 Years ]
    Occurrence of dose reduction of IMP within a patient due to treatment-emergent adverse events (TEAE)
  • Incidence of IMP treatment discontinuations due to toxicity [ Time Frame: up to 2 Years ]
    Occurrence of discontinuation of IMP within a patient due to treatment-emergent adverse events (TEAE)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2019)
  • Maximum Plasma Concentration (Cmax) of PK assessments [ Time Frame: up to 2 Years ]
  • Area under the curve (AUC) of PK assessments [ Time Frame: up to 2 Years ]
  • Objective Response Rate (ORR) [ Time Frame: up to 2 Years ]
    ORR defined as the proportion of patients in whom a CR or PR is observed as best overall response; according to RECIST 1.1
  • Disease Control Rate (DCR) [ Time Frame: up to 2 Years ]
    DCR defined as the proportion of patients in whom a CR or PR or SD (assessed at least 6 weeks after first dose) is observed as best overall response; according to RECIST 1.1
  • Duration of Response (DOR) [ Time Frame: up to 2 Years ]
    DOR defined as the time from first objective response (CR or PR) to the date of the first occurrence of objective tumor progression (PD); according to RECIST 1.1
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 23, 2019)
  • immune Objective Response Rate (iORR) [ Time Frame: up to 2 Years ]
    iORR defined as the proportion of patients in whom a iCR or iPR is observed as best overall response. • iDCR defined as the proportion of patients in whom a iCR or iPR or iSD (assessed at least 6 weeks after first dose) is observed as best overall response; according to iRECIST
  • immune Disease Control Rate (iDCR) [ Time Frame: up to 2 Years ]
    iDCR defined as the proportion of patients in whom a iCR or iPR or iSD (assessed at least 6 weeks after first dose) is observed as best overall response; according to iRECIST
  • immune Duration of Response (iDOR) [ Time Frame: up to 2 Years ]
    iDOR defined as the time from first objective response (iCR or iPR) to the date of the first occurrence of objective tumour progression (iCPD); according to iRECIST
  • Progression Free Survival (PFS) time [ Time Frame: up to 3 Years ]
    PFS defined as the time from first dose of IMP to first occurrence of objective tumor progression (per RECIST 1.1), or death from any cause, whichever occurs first
  • Overall Survival (OS) time [ Time Frame: up to 3 Years ]
    OS defined as the time from first dose of IMP to death from any cause
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy Trial of BNT411
Official Title  ICMJE Phase 1/2a, First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety, PK, PD, 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 ES-SCLC
Brief Summary 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 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 Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Solid Tumor
  • Extensive-stage Small Cell Lung Cancer
Intervention  ICMJE
  • Drug: BNT411
    intravenous
  • Drug: Atezolizumab
    intravenous
  • Drug: Carboplatin
    intravenous
  • Drug: Etoposide
    intravenous
Study Arms  ICMJE
  • Experimental: Part 1A - monotherapy dose escalation
    BNT411 monotherapy
    Intervention: Drug: BNT411
  • Experimental: Part 1B combination dose escalation
    BNT411 in combination with atezolizumab, carboplatin and etoposide
    Interventions:
    • Drug: BNT411
    • Drug: Atezolizumab
    • Drug: Carboplatin
    • Drug: Etoposide
  • Experimental: Part 2 expansion cohorts
    BNT411 either as monotherapy or in combination with other anti-cancer agents
    Intervention: Drug: BNT411
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 23, 2019)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2023
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

For Part 1A:

  • Histologically confirmed solid tumor (cytology is allowed for NSCLC 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 chemotherapy-naïve ES-SCLC (per the Veterans Administration Lung Study Group [VALG] staging system).

  • Treatment-free for at least 6 months since last chemo/radiotherapy, among those treated (with curative intent) with prior chemo/radiotherapy for LS SCLC.
  • Has no interstitial lung disease or active, non-infectious pneumonitis.

For Both Part 1A and Part 1B 5. Male and female ≥ 18 years of age. 6. 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.

7. ECOG performance status of 0 to 1. 8. Measurable disease according to RECIST 1.1. 9. Able to receive the first administration of trial treatment within 42 days from the last documented disease progression.

10. Adequate coagulation function at Screening as determined by:

a. International normalized ratio (INR) or prothrombin time ≤1.5 x upper limit normal (ULN; unless on therapeutic anticoagulants with values within therapeutic window), b. Activated partial thromboplastin time (aPTT) ≤1.5 x ULN (unless on therapeutic anticoagulants with values within therapeutic window).

11. Adequate hematologic function at Screening as determined by:

a. White blood count (WBC) ≥3 x 109/L b. Absolute neutrophil count (ANC) ≥1.5 x 109/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) c. Platelet count ≥100 x 109/L d. Hemoglobin (Hgb) ≥9.0 g/dL (may not transfuse or use erythropoietin to obtain this Hgb level).

12. Adequate hepatic function at Screening as determined by:

a. Total bilirubin ≤ 1.5 mg/dL (or ≤ 2.0 mg/dL for patients with known Gilbert's syndrome) b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ALT) ≤2.5 x ULN; or ≤5 x ULN in patients with metastatic liver disease 13. Adequate renal function at Screening as determined by:

a. Glomerular filtration rate (GFR) ≥60 mL/min/1.73 m²- 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; multiply it by 0.742 if the patient is female; multiply it by 1.212, if the patient is African-American (Levey et al., 1999).

14. Able to attend trial visits as required by the protocol. 15. 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 (Section 10.4) can be considered as not having reproductive potential.

16. 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.

17. A man who is sexually active with a woman of childbearing potential 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 (refer Section 10.4 for information on effective contraceptive methods).

18. All patients must provide an FFPE (Formalin Fixed Paraffin Embedded) from the latest available archival tumor tissue. If such tissue cannot be provided, the sponsor approval of enrollment is needed.

Exclusion Criteria:

Prior and Concomitant Therapy:

  • Has received prior systemic therapy with a TLR7 agonist
  • Has received anti-cancer chemotherapy, molecular-targeted drugs, radiotherapy, immunotherapy (e.g., vaccines, or cytokines), or investigational agents within the 28 days prior to the first dose of BNT411.
  • 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 3A4 and 3A5 (e.g., CYP3A4, CYP3A5).
  • Has had major surgery within the 4 weeks before the first dose of BNT411.
  • Ongoing or active infection requiring intravenous treatment with anti-infective therapy that has been administered less than two weeks prior to first dose of study treatment.
  • Has side effects of any prior therapy or procedures for any medical condition not recovered to NCI CTCAE v.5 grade ≤1.

Medical Conditions 8. Current evidence of new or growing brain or spinal metastases during screening. Patients with known brain or spinal metastases may be eligible if they:

a. had radiotherapy, surgery or stereotactic surgery for the brain or spinal metastases, b. have no neurological symptoms (excluding Grade ≤2 neuropathy), c. have stable brain or spinal disease on the CT or MRI scan within 4 weeks before signing the informed consent, d. must not be undergoing acute corticosteroid therapy or steroid taper. Chronic steroid therapy is acceptable provided that the dose is stable for the last 14 days prior to screening (≤ 10 mg prednisone daily or equivalent), f.e. spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.

Notes: Subjects with central nervous system symptoms should undergo a Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) of the brain to exclude new or progressive brain metastases.

9. 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.

10. Has effusions (pleural, pericardial, or ascites) requiring drainage. 11. Has retinal detachment, current/history of anterior/intermediate/posterior uveitis (including Vogt-Koyanagi-Harada syndrome, , current keratitis, thyroid-associated orbitopathy, idiopathic orbital inflammation, ischemic retinopathy (including glaucoma associated retinopathy), retinal vascular disease (e.g retinal vein occlusion, retinal artery occlusion), severe non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), cataract (according to AREDS lens grading system >2) 12. Has a fever ≥38°C within 3 days before signing the ICF. 13. 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.

14. Known history of seropositivity for human immunodeficiency virus (HIV) with CD4+ T-cell (CD4+) counts <350 cells/uL and with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections.

15. Known history/positive serology for hepatitis B requiring active antiviral 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.

16. Active Hepatitis C virus (HCV) infection; patients who have completed curative antiviral treatment with HCV viral load below the limit of quantification are allowed.

17. Has a known hypersensitivity to a component of BNT411 drug product, or another similar compound.

18. 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) Note: should be discussed with Medical Monitor in case of uncertainties.

Other Comorbidities 19. Has abnormal electrocardiograms (ECGs) that are clinically significant, such as QT prolongation >480 ms.

20. 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.

    21. 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.

    22. Is pregnant or breastfeeding.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: BioNTech clinical trials patient information +49 6131 9084 ext 1919 patients@biontech.de
Contact: BioNTech clinical trial information desk +49 6131 9084 ext 0 info@biontech.de
Listed Location Countries  ICMJE Germany,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04101357
Other Study ID Numbers  ICMJE BNT411-01
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party BioNTech SE ( BioNTech Small Molecules GmbH )
Study Sponsor  ICMJE BioNTech Small Molecules GmbH
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: BioNTech Responsible Person BioNTech SE
PRS Account BioNTech SE
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP