AHEAD-MERIT: This study is evaluating an anticancer vaccine when given in combination with immunotherapy, compared to immunotherapy alone, in people with recurrent or metastatic head and neck squamous cell carcinoma which is HPV16+ and expresses PD-L1An Open Label Phase II Randomized Trial of BNT113 in Combination With Pembrolizumab Versus Pembrolizumab Monotherapy as a First Line Therapy in Patients With Unresectable Recurrent, or Metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) Which is Positive for Human Papilloma Virus 16 (HPV16+) and Expresses PD-L1

Exclusion

Medical conditions:

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

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

  • Ongoing or active infection which requires systemic treatment with antibiotics on the first dose of trial treatment.
  • 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.
  • Arterial thrombosis or pulmonary embolism within ≤6 months before the start of trial treatment, if not on a stable dose of anticoagulants or if in the opinion of the investigator contra-indicates trial inclusion.
  • Evidence or history of interstitial lung disease that, in the opinion of the investigator, is a contraindication for treatment with pembrolizumab, or active non-infectious pneumonitis.
  • Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management. Patients with arterial hypertension need to be on stable anti-hypertensive medication for at least 4 weeks prior to trial entry.
  • Known primary immunodeficiencies.
  • Evidence or history of significant autoimmune disease that (a) required treatment with systemic immunosuppressive treatments, (b) was associated with ongoing treatment with corticosteroids, or (c) was associated with a record of significant end-organ dysfunction (even if transient), which in the opinion of the investigator may suggest increased risk for immune-related AEs.
  • Patients with prior allogeneic stem cell or solid organ transplantation.
  • Any other disease, metabolic dysfunction, physical examination finding, and/or laboratory finding giving reasonable suspicion of a disease or condition that in the opinion of the investigator contraindicates the use of an investigational drug or may render the patient at high risk for 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 major surgery planned during the time of trial participation.

• Patients who have a known history or a positive test at screening of any of the following:

  1. Human immunodeficiency virus (HIV) 1 or 2. Inclusion is allowed if HIV 1/2 infection is adequately controlled and stable on a highly effective antiviral regimen.
  2. Hepatitis B infection, as defined by the presence of hepatitis B surface antigen (HbsAg) or hepatitis B virus (HBV) DNA positivity. Testing of HBV DNA is mandatory if hepatitis B core antibody is positive.
  3. Hepatitis C (unless considered cured).
• 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 treatment including corticosteroid treatment (prednisone >10 mg daily orally [PO] or intravenously [IV], or equivalent) in the 7 days prior to the first dose of trial treatment.
  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 have not resolved prior to the first dose of BNT113 or that pose an additional risk of on-trial complications, per investigator's assessment, or (c) associated with toxicity that resulted in discontinuation of the immune-modulating agent and that poses an additional risk of on-trial complications, per investigator's assessment.
  3. Prior treatment with live attenuated vaccines within 4 weeks before the first dose of BNT113.
  4. 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.
  5. Ongoing treatment with therapeutic PO or IV antibiotics. • Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) may be enrolled.
• 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 or 5 half-lives of the agent (whichever is longer) before the first dose of BNT113.

• Treatment with non-systemic anti-cancer therapy (e.g., radiotherapy or surgery) within 2 weeks prior to randomization.

  • Note: Prior treatment with bone resorptive therapy, such as bisphosphonates (e.g., pamidronate, zoledronic acid) and denosumab, is allowed.

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 no evidence of clinical or radiological progression within 4 weeks before signing the informed consent,
  4. do not require steroid therapy within 7 days before randomization or are undergoing slow steroid tapering, currently at doses ≤10 mg and neurologically stable.
  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 (rescreening is allowed once).
• Patients with substance abuse or known medical, psychological, or social conditions that in the opinion of the investigator 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) or sponsor. For patients meeting this criterion, a prospective exception and eventual contingencies to be put in place may be defined on a case-by-case basis by the local Institutional Review Board.

Tumor-related conditions:

• Patients that have disease suitable for local therapy administered with curative intent.
• Patients that have a life expectancy of less than 3 months and/or have rapidly progressive disease, as assessed by the treating investigator.
• Patients with high-burden of visceral metastatic disease or location in anatomically critical areas (e.g., causing significant biliary or respiratory obstruction), that in the opinion of the investigator may benefit from treatment with chemotherapy.