Safety and Efficacy of VB10.16 and Pembrolizumab in Patients With Head-Neck Squamous Cell Carcinoma

A Phase 1/2, Open-label Trial to Evaluate Safety, Immunogenicity, and Anti-tumor Activity of VB10.16 in Combination With Pembrolizumab in Patients With Unresectable Recurrent or Metastatic HPV16-positive Head and Neck Squamous Cell Carcinoma

This is a multi-center study in patients with un-resectable Recurrent or Metastatic HPV16-positive oropharyngeal Head and Neck Squamous Cell Carcinoma (HNSCC). The trial is designed to investigate VB10.16, an investigational therapeutic DNA vaccine in combination with another medicine, pembrolizumab, which is the standard of care for patients with previously untreated metastatic or resectable recurrent PD-L1 positive HNSCC. The study is divided in 2 parts:

• Phase 1: Dose escalation to evaluate safety and determine the recommended phase 2 dose (RP2D) of VB10.16
• Phase 2: Randomized comparison of VB10.16 in combination with pembrolizumab versus pembrolizumab monotherapy The goal of Phase 1 is to evaluate the safety and tolerability of the combined treatment and to decide on the dose of VB10.16 to be used in the second part of the trial. The randomized Phase 2 will consist of 2 parallel arms exploring VB10.16 at the selected RP2D from the escalation phase in combination with pembrolizumab SoC (experimental arm, Arm A), versus pembrolizumab alone (control arm, Arm B).

This Phase 1/2, open-label, dose-escalation and randomized trial is designed to evaluate the safety, tolerability, anti-tumor activity and immunogenicity of VB10.16 in combination with pembrolizumab in patients with HPV16-positive, PD-L1-positive unresectable recurrent or metastatic (r/m) oropharyngeal HNSCC, who are eligible for pembrolizumab monotherapy as standard of care (SoC) in the first-line setting. The trial consists of 2 consecutive phases with separate patient groups and is designed to determine the RP2D of VB10.16 in combination with pembrolizumab through dose-escalation of 3 mg, 6 mg, and 9 mg VB10.16, and to evaluate efficacy of the RP2D of VB10.16 when combined with pembrolizumab compared to pembrolizumab alone in Phase 2.

Phase 1: The dose escalation Phase 1 will consist of 3 dosing cohorts to evaluate VB10.16 at 3 mg (Cohort 1), 6 mg (Cohort 2), and 9 mg (Cohort 3). The 3 mg cohort will utilize a partial accelerated titration approach with a single patient41. The 6 mg cohort will follow a standard titration with 3 patients, and the 9 mg cohort will include a minimum of 6 patients to safety-clear the dose as a potential RP2D in the randomized phase.

Phase 2: The randomized Phase 2 will consist of 2 parallel arms exploring VB10.16 at the selected RP2D from the escalation phase in combination with pembrolizumab SoC (experimental arm, Arm A), versus pembrolizumab alone (control arm, Arm B). Allocation will be 1:1 by centralized block randomization, stratified by PD-L1 expression (CPS 1-19 versus ≥20) and ECOG PS (0 versus 1) Treatment duration is up to 2 years or until disease progression, unacceptable toxicity, withdrawal of consent, or death.

KEY INCLUSION CRITERIA:

• ≥18 years of age (or as per national legal age of trial consent, whichever is higher) at date of signing the informed consent form (ICF).
• Histologically or cytologically confirmed r/m HNSCC, located in the oropharynx, considered incurable by local therapy and eligible for monotherapy with pembrolizumab.
• HPV16 positivity of r/m oropharyngeal HNSCC confirmed by designated central laboratory.

laboratory.

• PD-L1 positivity (CPS ≥1) using the validated PD-L1 IHC 22C3 pharmDx (DAKO) assay.
• Primary tumor location in the oropharynx.
• At least 1 measurable lesion per RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
• Life expectancy of ≥3 months, as determined by Gustave Roussy Immuno (GRIm) score 0-1.

KEY Exclusion criteria:

HNSCC DISEASE

• Has disease that is suitable for local therapy with curative intent.
• Has progressive disease ≤6 months after completion of curatively intended concurrent chemoradiotherapy for locoregionally advanced r/m oropharyngeal HNSCC.
• Primary tumor site of the oral cavity, hypopharynx, larynx or nasopharynx (any histology).
• Rapidly progressing disease (e.g., tumor bleeding, uncontrolled tumor pain) in the opinion of the investigator. PRIOR, CONCURRENT, OR FUTURE INTERVENTIONS
• Has received prior palliative radiotherapy within 2 weeks of start of trial treatment or has a prior history of radiation pneumonitis.
• Any prior investigational or approved systemic antineoplastic drug or invasive medical device (including ICIs), either as monotherapy or as part of a combination regimen administered in the r/m HNSCC setting.
• Prior solid organ or tissue transplantation (except corneal transplant).
• Prior autologous or allogeneic hematopoietic stem cell transplantation (HSCT).
• Prior chimeric antigen receptor T (CAR-T) cell therapy.
• Prior therapy with a monoclonal or bispecific antibody or antibody fragment (or other molecules with similar mechanism of action) that engages T-cells.
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose of trial intervention.
• Administration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine within 30 days prior to trial treatment start.
• Prior administration with a therapeutic HPV16 vaccine.
• Patients receiving systemic immunosuppression with immunosuppressive agents such as cyclosporine, azathioprine, methotrexate, or tumor necrosis factor alpha (TNF-α) blockers for any concurrent condition.
• Chronic administration of systemic corticosteroids: prednisone >10 mg daily (or dose equivalent).
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), including pembrolizumab in the locoregional setting.
• Primary immunodeficiency, other immunosuppressive disorder, and/or other causes of immunosuppression.
• Has known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during trial screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment. Accordingly, routine brain MRI at screening is not mandatory for all patients, only for those with previously treated but stable brain metastases.
• New (≤6 months), progressive and/or symptomatic brain metastases.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.