Clinical Trials /

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

NCT04101357

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy Trial of BNT411
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: BNT411-01
  • NCT ID: NCT04101357

Conditions

  • Solid Tumor
  • Extensive-stage Small Cell Lung Cancer

Interventions

DrugSynonymsArms
BNT411Part 1A - monotherapy dose escalation
AtezolizumabPart 1B combination dose escalation
CarboplatinPart 1B combination dose escalation
EtoposidePart 1B combination dose escalation

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Part 1A - monotherapy dose escalationExperimentalBNT411 monotherapy
  • BNT411
Part 1B combination dose escalationExperimentalBNT411 in combination with atezolizumab, carboplatin and etoposide
  • BNT411
  • Atezolizumab
  • Carboplatin
  • Etoposide
Part 2 expansion cohortsExperimentalBNT411 either as monotherapy or in combination with other anti-cancer agents
  • BNT411

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of DLTs
Time Frame:21 Days
Safety Issue:
Description:Occurrence of DLTs within a patient during the DLT evaluation period

Secondary Outcome Measures

Measure:Maximum Plasma Concentration (Cmax) of PK assessments
Time Frame:up to 2 Years
Safety Issue:
Description:
Measure:Area under the curve (AUC) of PK assessments
Time Frame:up to 2 Years
Safety Issue:
Description:
Measure:Objective Response Rate (ORR)
Time Frame:up to 2 Years
Safety Issue:
Description:ORR defined as the proportion of patients in whom a CR or PR is observed as best overall response; according to RECIST 1.1
Measure:Disease Control Rate (DCR)
Time Frame:up to 2 Years
Safety Issue:
Description: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
Measure:Duration of Response (DOR)
Time Frame:up to 2 Years
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:BioNTech Small Molecules GmbH

Trial Keywords

  • Solid Tumor
  • Extensive-stage Small Cell Lung Cancer

Last Updated

July 24, 2020