Overview

This first-in-human (FIH) trial for BNT116 aims to establish the safety profile and a safe dose for BNT116 monotherapy as well as for BNT116 in combination with approved medicinal products and/or in combination with investigational medicinal products (IMPs) including, but not limited to, cemiplimab, docetaxel, carboplatin, paclitaxel, BNT316 (an anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] antibody), an anti-B7-H3 antibody conjugated to a topoisomerase I inhibitor, or an anti-human epidermal growth factor receptor 3 (HER3) antibody conjugated to a topoisomerase I inhibitor in patients with non-small cell lung cancer (NSCLC).

The trial will comprise of several cohorts for dose confirmation in monotherapy as well as in combinations of BNT116 as mentioned above.

The trial will enroll patients with NSCLC in advanced or metastatic stage in Cohorts 1 to 4 and Cohorts 7 to 9, unresectable NSCLC Stage III in Cohort 5, and resectable NSCLC of Stage II and III in Cohort 6.

Eligibility

Key Inclusion Criteria:

• Patients must have histologically confirmed NSCLC and measurable disease by RECIST v1.1. Note: Patients in Cohort 1 and Cohort 5 do not have to present with measurable disease.
  1. Patients must present with unresectable Stage III or metastatic Stage IV NSCLC by American Joint Commission on Cancer (AJCC) Cancer Staging Manual, Eighth Edition.

     EXCEPT

  2. Patients in Cohort 5 must present with unresectable Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition before receiving pre-trial chemoradiotherapy.
  3. Patients in Cohort 6 with the initial diagnosis of resectable Stage II and Stage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition.
• Patients in Cohorts 2, 4, 5, and 6 must be able to tolerate (additional) anti-PD-1

  therapy (i.e., did not permanently discontinue anti-programmed death protein 1 [PD-1] / programmed death ligand 1 [PD-L1] therapy due to toxicity).

• Patients must have an Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1, except for patients in Cohorts 1, 4, and 5 who are eligible with an ECOG-PS of 0-2.

Cohort-specific inclusion criteria:

Cohort 1:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen as well as one other line of systemic therapy (except if a patient is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor and/or another line of systemic therapy). Note: Patients newly enrolled in Cohort 1B under clinical trial protocol v5.0 and subsequent versions of the clinical trial protocol must consent to mandatory blood sampling for peripheral blood mononuclear cells (PBMCs).
• Patients who are to start cemiplimab at Cycle 3 must present with PD-L1 expression of tumor proportion score (TPS) ≥1% in tumor cells (as determined locally).

Cohort 2:

• Patients must present with PD-L1 expression of tumor proportion score (TPS) ≥50% in tumor cells (as determined locally prior to inclusion in this trial).
• Patients must present with progressive disease either
  1. in the advanced or metastasized stage of NSCLC: while on a PD-1/PD-L1 inhibitor therapy or within 6 months of termination of this treatment as first-line treatment. Or
  2. be refractory to ongoing adjuvant therapy/maintenance treatment after CRT with a PD-1/PD-L1 inhibitor that has been given for at least 3 months in monotherapy (i.e., after an initial combination therapy) before being enrolled into this trial.

Cohort 3:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a patient is not candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
• Patients must present with progressive disease.

Cohort 4:

• Patients' who are not candidates for chemotherapy as first-line treatment for the advanced or metastasized stage of NSCLC may be enrolled if presenting with PD-L1 expression: TPS ≥1% in tumor cells (as determined locally).

Cohort 5:

• Patients' NSCLC must have been considered unresectable due to patients' condition and/or tumor-related factors and the patients must have undergone chemoradiotherapy before entering the trial.

Cohort 6:

• Patients' NSCLC must be considered technically and medically resectable.
• Patients must be considered eligible for neo-adjuvant treatment.

Cohort 7:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a patient is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor). Note 1: Patients may have received prior therapy targeting CTLA-4, lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain (TIGIT), vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR) inhibitor as monotherapy or part of a combination therapy. Note 2: If the patient's prior therapies included a CTLA-4 inhibitor, the patient must be able to tolerate (additional) treatment with the CTLA-4 inhibitor.
• Patients must present with progressive disease at trial enrollment.
• Patients must consent to mandatory blood sampling for PBMCs.

Cohorts 8 & 9:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy regimen (except if a patient is not a candidate for a platinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).
• Patients must present with progressive disease at trial enrollment.

Key Exclusion Criteria:

• Ongoing active systemic treatment against NSCLC.
• Presence of a driver mutation for which approved target therapies are available except if the patient is not a candidate for the respective targeted therapy.
• Ongoing or recent evidence (within the last 5 years) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may suggest risk for immune-related adverse events. Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related hypothyroidism who are in remission, or on a stable dose of thyroid-replacement hormone, vitiligo, or psoriasis may be included.
• Current evidence of new or growing brain or spinal metastases during screening. Patients with leptomeningeal disease are excluded. Patients with known brain or spinal metastases may be eligible for all Cohorts, except for Cohort 5 and 6, if

  they

• had radiotherapy or another appropriate therapy for the brain or spinal metastases,

  AND

• have no neurological symptoms that can be attributed to the current brain lesions, AND
• have stable brain or spinal disease on the computed tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the informed consent (confirmed by stable lesions on two scans at least 4 weeks apart), AND
• do not require steroid therapy for the treatment of brain or spinal metastases within 14 d before the first dose of trial treatment. Note: Spinal bone metastases (i.e., of the vertebrae) are allowed, unless imminent fracture or cord compression is anticipated.
• Systemic immune suppression:
• Current use of chronic systemic steroid medication (≤5 mg/day prednisolone equivalent is allowed); patients using physiological replacement doses of prednisone for adrenal or pituitary insufficiency are eligible. Note: Steroid medication given for supportive or prophylactic reasons during CRT for patients in Cohort 5 needs to be tapered to ≤5 mg/day prednisolone equivalent at latest on the day before the trial treatment starts.
• Other clinically relevant systemic immune suppression within the last 3 months before trial enrollment.
• 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.
• Prior splenectomy.
• History/risk of interstitial lung disease or low baseline lung function (baseline pulse oximetry of less than 92% oxygen saturation [SpO2] without additional oxygen).

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply to all or some patients depending on the cohort.