AHEAD-MERIT

• Patients are pregnant or breastfeeding.
• Patients present primary tumor site of nasopharynx (any histology).

• Patients with uncontrolled intercurrent illness, including but not limited to:

  1. Ongoing or active infection which requires systemic treatment with antibiotics or corticoid therapy within 14 days before the first dose of trial treatment.
  2. Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), myocardial infarction within 3 months before screening, unstable angina pectoris, or cardiac arrhythmia.
  3. Arterial thrombosis or pulmonary embolism within ≤6 months before the start of trial treatment.
  4. Known recent history (in the past 5 years) or presence of significant pulmonary conditions such as uncontrolled chronic lung disease, or any evidence of interstitial lung disease, or active, non-infectious pneumonitis.
  5. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management.
  6. Known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T negative severe combined immunodeficiency [SCID]) or combined T and B cell immunodeficiencies (e.g., T and B negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency).

  7. Ongoing or recent evidence (within the past year) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may suggest risk for immune-related adverse events (AEs).

     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.

  8. Non-healing wound, skin ulcer (of any grade), or bone fracture.
  9. Patients with prior allogeneic stem cell or solid organ transplantation.
  10. Patients with the following risk factors for bowel perforation (e.g., history of acute diverticulitis or intra-abdominal abscess in the last 3 years; history of gastrointestinal obstruction or abdominal carcinomatosis).
  11. Patients with uncontrolled Type 1 diabetes mellitus. Note: Patients controlled on a stable insulin regimen are eligible.
  12. Patients with uncontrolled adrenal insufficiency.
  13. Any other disease, metabolic dysfunction, physical examination finding, and/or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or may render the patient at high risk for treatment of complications.
• Patients with a known allergy, hypersensitivity, or intolerance to BNT113 or its excipients, or to pembrolizumab or its excipients.
• Patients who have had a splenectomy.
• Patients who have had major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, or have not fully recovered from surgery, or have a surgery planned during the time of trial participation.

• Patients who have a known history (testing not required) or has a positive test at screening of any of the following:

  1. Human immunodeficiency virus (HIV) 1 or 2.
  2. Hepatitis B (carrier or active infection).
  3. Hepatitis C (unless considered cured 5 years post curative anti-viral therapy).
• Patients with another primary malignancy that has not been in complete 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, non-invasive basal or non-invasive squamous cell skin cancer, localized prostate cancer, non-invasive superficial bladder cancer or breast ductal carcinoma in situ).
• Patients with any condition for which, in the opinion of the investigator, participation would not be in the best interest of the patient (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

Prior/concomitant therapy:

• Patients who have received or currently receive the following therapy/medication:

  1. Chronic systemic immunosuppressive corticosteroid treatment (prednisone >5 mg daily orally [PO] or IV, or equivalent) during the trial. Note: Replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is permitted.
  2. Prior treatment with other immune modulating agents that was (a) within fewer than 4 weeks (28 days) or 5 half-lives of the agent (whichever is longer) prior to the first dose of BNT113, or (b) associated with immune-mediated AEs that were Grade ≥1 within 90 days prior to the first dose of BNT113, or (c) associated with toxicity that resulted in discontinuation of the immune-modulating agent.
  3. Prior treatment with other immune modulating agents for any non-cancer disease within 4 weeks or 5 half-lives of the agent (whichever is longer) before the first dose of BNT113.
  4. Prior treatment with live attenuated vaccines within 4 weeks before the first dose of BNT113.
  5. Prior treatment with an investigational drug (including investigational vaccines) within 4 weeks or 5 half-lives of the agent (whichever is longer) before the planned first dose of BNT113.
  6. Therapeutic PO or IV antibiotics within 14 days prior to enrollment. • Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) may be enrolled.
• Prior anti-cancer therapy in the metastatic or in the unresectable recurrent HNSCC setting.
• Prior treatment with anti-cancer immunomodulating agents, such as blockers of programmed death receptor-1 (PD 1), PD-L1, tumor necrosis factor receptor superfamily member 9 (TNRSF9, 4 1BB, CD137), OX 40, therapeutic vaccines, cytokine treatments, or any investigational agent within 4 weeks before the first dose of BNT113.

• Treatment with other anti-cancer therapy including chemotherapy, radiotherapy with curative intent, major surgery with curative intent or biological cancer therapy within 6 months prior to randomization. Adjuvant hormone therapy used for breast cancer in long term remission is allowed.

  • Note 1: Palliative radiotherapy and palliative surgery are allowed.
  • Note 2: Prior treatment with bone resorptive therapy, such as bisphosphonates (e.g., pamidronate, zoledronic acid) and denosumab, is allowed assuming that the patients have been on stable doses for ≥4 weeks prior to first dose of trial treatment.

Other comorbidities:

• Current evidence of Common Terminology Criteria for Adverse Events (CTCAE, v5.0) Grade >1 toxicity before the start of treatment, except for hair loss and those Grade 2 toxicities listed as permitted in other eligibility criteria. Patients with Grade 2 neuropathy may be eligible at investigator's discretion.

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

  1. had radiotherapy or another appropriate therapy for the brain or spinal metastases,
  2. have no neurological symptoms (excluding Grade ≤2 neuropathy),
  3. have stable brain or spinal disease on the computer tomography (CT) or magnetic resonance imaging (MRI) scan within 4 wks before signing the informed consent,
  4. do not require steroid therapy within 7 d before randomization,
  5. spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.

Other exclusions:

• Patients who have previously been enrolled in this trial.
• Patients with substance abuse or known medical, psychological, or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial results.
• Patients affiliated with the investigational site (e.g., a close relative of the investigator or dependent person, such as an employee or student of the trial site).