Overview

An open-label, controlled, multi-site, interventional, 2-arm, Phase II trial of BNT113 in combination with pembrolizumab vs pembrolizumab monotherapy as first line treatment in patients with unresectable recurrent or metastatic HPV16+ HNSCC expressing programmed cell death ligand -1 (PD-L1) with combined positive score (CPS) ≥1.

This trial has two parts.

Part A, an initial non-randomized Safety Run-In Phase to confirm the safety and tolerability at the selected dose range level of BNT113 in combination with pembrolizumab.

Part B, the Randomized part of the trial to generate pivotal efficacy and safety data of BNT113 in combination with pembrolizumab versus pembrolizumab monotherapy in the first line setting in patients with unresectable recurrent or metastatic HPV16+ HNSCC expressing PD-L1 with CPS ≥1.

For Part B, an optional pre-screening phase is available for all patients where patients' tumor samples may be submitted for central HPV16 DNA and central PD-L1 expression testing prior to screening into the main trial.

Eligibility

Inclusion Criteria:

        Pre-screening phase (optional - patients can alternatively perform tumor biomarker testing
        as part of the main screening phase):
          -  Patients must sign the written pre-screening informed consent form (ICF) before any
             pre-screening procedures.
          -  Patients must have histologically confirmed recurrent or metastatic HNSCC with no
             prior systemic anticancer therapy administered in the recurrent or metastatic (R/M)
             setting.
          -  Patients have a clinical situation at a relatively high risk of developing R/M
             disease.
          -  Patients do not meet any exclusion criteria for the main clinical trial, except for
             time-dependent (e.g., prior systemic treatment in the prior 6 months) or potentially
             reversible conditions that in the opinion of the investigator will be resolved prior
             to potential enrollment into the main phase.
        Main trial:
          -  Patients must sign the written informed consent form before any screening procedure.
             Informed consent must be documented before any trial-specific screening procedure is
             performed.
          -  Patients must be aged ≥18 years on the date of signing the informed consent.
          -  Patients must be willing and able to comply with scheduled visits, treatment schedule,
             laboratory tests, and other requirements of the trial.
          -  Patients who present histologically confirmed recurrent or metastatic HPV16+ HNSCC
             that is considered incurable by local therapies.
          -  Patients who have a tumor that expresses PD-L1 [CPS ≥1] as determined by the approved
             test PD-L1 IHC 22C3 pharmDx kit performed and evaluated according to the
             manufacturer's specifications and relevant regulatory approvals.
          -  The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and
             larynx.
          -  Patients must not have had prior systemic anticancer therapy administered in the
             incurable recurrent or metastatic setting. Systemic therapy which was completed more
             than 6 months prior to randomization, if given as part of multimodal treatment for
             locally advanced disease, is allowed.
          -  Patients who have measurable disease based on RECIST 1.1 as determined by the site and
             confirmed by BICR. Tumor lesions situated in a previously irradiated area may be
             considered measurable, if progression has been demonstrated in such lesions disease by
             RECIST 1.1.
          -  Patients have Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
          -  Patients have adequate bone marrow function as defined by hematological parameters.
          -  Patients have adequate hepatic function.
          -  Patients should have adequate kidney function, assessed by the estimated glomerular
             filtration rate (eGFR) ≥30 mL/min/1.73m^2 using the Chronic Kidney Disease
             Epidemiology Collaboration (CPK-EPI) equation.
          -  Patients should be stable with adequate coagulation, as determined by the
             investigator.
          -  All patients must provide a tumor tissue sample (formalin fixed paraffin embedded
             [FFPE] blocks or both slides and curls) from archival tissue, or fresh biopsy if a
             biopsy is performed as part of the patient's standard clinical practice before the
             first dose of trial treatment.
          -  Women of childbearing potential (WOCBP) must not be pregnant. WOCBP, male patients who
             are sexually active with WOCBP and female partners of male patients should use a
             highly effective method of contraception up to at least 6 months after receiving the
             last dose of trial treatment, and should agree not to donate eggs (ova, oocytes) or
             sperm.
        Exclusion Criteria:
        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.