Evaluation of Safety, Immunogenicity, and Anti-tumor Activity of VB10.16 and Pembrolizumab in HPV16-positive Head and Neck Squamous Cell Carcinoma

Trial ID: 2022-503055-26-00
Protocol: VB-C-03
Sponsor: Nykode Therapeutics ASA

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Diseases & Conditions

Squamous cell carcinoma of head and neck

Objectives

The primary objective of this study is to evaluate the **clinical efficacy** of VB10.16 in combination with a fixed dose of pembrolizumab in patients with unresectable recurrent or metastatic HPV16-positive head and neck squamous cell carcinoma. This evaluation is crucial for determining the potential therapeutic benefits of this combination therapy in a patient population with limited treatment options.

Secondary objectives include:

Expansion phase: To evaluate the anti-tumor activity of VB10.16 in combination with a fixed dose of pembrolizumab.
Expansion phase: To assess the clinical efficacy of VB10.16 in combination with a fixed dose of pembrolizumab.
Full trial: To characterize the safety profile of VB10.16 in combination with a fixed dose of pembrolizumab.
Full trial: To further evaluate the clinical efficacy of VB10.16 in combination with a fixed dose of pembrolizumab.
Full trial: To evaluate the immunogenicity of VB10.16 in combination with a fixed dose of pembrolizumab.

These secondary objectives aim to provide a comprehensive understanding of the treatment's safety, efficacy, and immunogenicity, which are essential for its potential clinical application.

Participants

The clinical trial involves a total of **8 participants** diagnosed with **unresectable recurrent or metastatic HPV16 positive oropharyngeal Head and Neck Squamous Cell Carcinoma**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific health criteria, including confirmed HPV16 positivity and PD-L1 positivity, as well as an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensured that participants have a histologically or cytologically confirmed diagnosis of recurrent or metastatic head and neck squamous cell carcinoma located in the oropharynx, which is deemed incurable by local therapy and eligible for monotherapy with pembrolizumab. Key inclusion criteria also required participants to have at least one measurable lesion per RECIST 1.1 guidelines.

Plans and Procedures

The clinical trial is designed as a **Phase 1/2a, open-label, dose-finding study** to evaluate the 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. The trial is structured into two main phases: the escalation phase and the expansion phase. The escalation phase aims to determine the maximum recommended phase 2 dose (RP2D) by assessing the safety of doses equal to or greater than 3 mg of VB10.16. The expansion phase will focus on identifying the optimal biological dose (OBD) from the selected RP2Ds and evaluating the clinical efficacy of the combination therapy.

The trial employs a **randomized, controlled design** with an estimated duration extending until October 2027. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, laboratory values, and HPV16 positivity. Following the screening, participants will be enrolled and randomized into the trial. Regular follow-up visits will be conducted to monitor safety, efficacy, and any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be made.

Participant involvement is expected to last throughout the trial duration, with specific timelines for each phase. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities (DLTs) during the escalation phase or adverse reactions leading to discontinuation in the expansion phase. The primary endpoints include the proportion of patients with DLTs, objective response rate (ORR), and changes in HPV16 E6/E7-specific T-cell responses. Secondary endpoints encompass disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Treatment

The clinical trial involves the administration of **KEYTRUDA** (pembrolizumab), a **concentrate for solution for infusion**. Pembrolizumab is a monoclonal antibody that targets the PD-1 receptor, used in the treatment of various cancers. In this study, it is provided as a 25 mg/mL concentrate, which is diluted and administered via intravenous infusion. The frequency and dosage of administration are determined based on the trial protocol, ensuring adherence to safety and efficacy standards. Participant compliance is monitored through regular assessments and documentation of infusion schedules.

Additionally, the trial includes the investigational product **VB10.16**, a **solution for injection**. VB10.16 is a nucleic acid-based therapeutic designed to elicit an immune response against HPV16-positive tumors. It is administered intramuscularly using the PharmaJet Stratis, a CE-certified needle-free injection system. The dosing regimen for VB10.16 is established during the dose-escalation phase of the trial, with the aim of identifying the maximum recommended phase 2 dose (RP2D) and the optimal biological dose (OBD). Compliance with the dosing schedule is closely monitored to ensure the integrity of the trial data.

No non-experimental treatments, such as standard-of-care therapy or placebo, are utilized in this study. The trial focuses on evaluating the safety, immunogenicity, and anti-tumor activity of the combination of VB10.16 and pembrolizumab in patients with unresectable recurrent or metastatic HPV16-positive head and neck squamous cell carcinoma. The study protocol outlines detailed procedures for drug administration, participant monitoring, and data collection to ensure the reliability and validity of the trial outcomes.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)**, which will be evaluated during the expansion phase and throughout the full trial. Additionally, the escalation phase will focus on the proportion of patients experiencing dose-limiting toxicities (DLTs) within 42 days, while the expansion phase will assess the proportion of patients who discontinue due to adverse reactions and changes from baseline in HPV16 E6/E7-specific T-cell responses, as measured by IFN-γ ELISpot in post-vaccination samples. The severity grade of adverse events (AEs) following treatment initiation will also be monitored.

Secondary endpoints will further evaluate the efficacy by measuring the Disease Control Rate (DCR), Duration of Response (DOR), Duration of Complete Response (DOCR), Duration of Disease Control (DODC), Time to Response (TTR), Progression-Free Survival (PFS), and Overall Survival (OS). The trial will also track the proportion of patients who remain progression-free and those who are alive. Changes from baseline in HPV16 E6/E7-specific T-cell responses will be assessed using IFN-γ ELISpot in post-vaccination samples. These endpoints will be measured at various timepoints throughout the trial to provide a comprehensive evaluation of the treatment's efficacy.

Inclusion and Exclusion Criteria

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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).
Platelets ≥100 × 109 /L (100,000/μL).
Neutrophils (absolute neutrophil count [ANC]) ≥1.5 × 109 /L (1,500/µL).
Patients capable of giving informed consent must provide signed and dated written informed consent prior to initiation of any study-related procedures
Hemoglobin ≥5.6 mmol/L (9.0 g/dL).
Total bilirubin ≤1.5 × upper limit of normal (ULN) (except Gilbert syndrome, then direct bilirubin ≤2 × ULN) or direct bilirubin ≤ULN for a patient with total bilirubin levels >1.5 × ULN
Aspartate transaminase (AST) ≤2.5 × ULN or ≤5 × ULN for a patient with liver metastases.
Alanine transaminase (ALT) ≤2.5 × ULN or ≤ 5 × ULN for a patient with liver metastases.
Alkaline phosphatase ≤2.5 × ULN or ≤5 × ULN for a patient with liver metastases.
International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless the patient is receiving anticoagulant therapy, in which case PT and partial thromboplastin time (PTT)/activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants.
Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 using the Cockroft-Gault formula.
Female patients of childbearing potential: negative serum pregnancy test (≤72 hours).
Female patients of childbearing potential must agree to use highly effective contraception throughout the trial (14 days prior to initiation of treatment for oral contraception), and for at least 120 days (according to the current version of the investigator’s brochure for pembrolizumab) after the last dose of pembrolizumab and up to 6 months after the last dose of VB10.16, whichever comes last. Male patients must agree to use male condoms during intercourse throughout the trial, and up to 3 months after the last dose of VB10.16, and must refrain from sperm donation in the same period. Highly effective forms of contraception include: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the trial drugs). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (calendar, symptothermal, post ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of contraception.
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.
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

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Exclusion Criteria

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.
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).
Administration of G-CSF/GM-CSF or transfusions with red blood cells, platelets, or plasma components ≤2 weeks prior to trial treatment start.
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.
History of major surgery within 4 weeks prior to the first dose of trial treatment or has not fully recovered from surgery-related effects, healings, or complications to ≤ Grade 1 (per Common Terminology Criteria for Adverse Events). Major surgery is considered as any procedure requiring general anesthesia or inpatient hospitalization. The investigator should consult with the medical monitor if uncertain whether a procedure qualifies as major surgery
Any planned major surgery.
Past or current malignancy other than inclusion diagnosis, except for: Malignancy treated with curative intent and with no known active disease present and has not received chemotherapy for at least 3 years before screening and felt to be at low risk for recurrence by the treating physician. Adequately treated breast ductal carcinoma in situ without evidence of disease. Adequately treated cervical carcinoma in situ, without evidence of disease. Adequately treated non-melanoma skin cancer without evidence of disease. Adequately treated superficial or in situ carcinoma of the bladder without evidence of disease. Prostatic intraepithelial neoplasia without evidence of prostate cancer..
Any current bleeding disorder, active bleeding, or bleeding diathesis.
Symptomatic congestive heart failure (Grade III or IV as classified by the New York Heart Association), unstable angina pectoris, or cardiac arrhythmia.
History of myocardial infarction ≤6 months prior to planned trial treatment start.
Uncontrolled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg), despite optimal medical management.
Any other significant cardiac disease(s) that, in the opinion of the investigator, is/are clinically significant and/or unacceptable.
Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
Primary immunodeficiency, other immunosuppressive disorder, and/or other causes of immunosuppression.
Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
Has a known history of human immunodeficiency virus (HIV) infection.
Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Any active, acute, or chronic infection that is uncontrolled and/or requires systemic treatment.
Known allergies, sensitivity, or intolerance to VB10.16 (active substance or to any of the excipients), pembrolizumab (active substance or to any of the excipients), or aminoglycosides (especially kanamycin).
Any history of intracerebral arteriovenous malformations, cerebral aneurysm, or stroke.
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.
Is currently participating in or has participated in a trial of an investigational agent or device in the r/m HNSCC setting.or to the first dose of trial treatment.
Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the trial or interfere with participation for the full duration of the trial, such that it is not in the best interest of the patient to participate, in the opinion of the treating investigator.
Has a known psychiatric or substance abuse disorder that would interfere with the patient’s ability to cooperate with the requirements of the trial.
Has a concomitant medical condition requiring receipt of a therapeutic anticoagulant that, in the opinion of the treating physician, would contraindicate administration of VB10.16 and tumor biopsies.
Female patients who are pregnant or breastfeeding.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	27 Oct 2023	3
France	Recruiting	27 Oct 2023	20
Germany	Recruiting	27 Oct 2023	15
Hungary	Recruiting	27 Oct 2023	6
Norway	Recruiting	27 Oct 2023	7
Poland	Recruiting	27 Oct 2023	13
Spain	Recruiting	27 Oct 2023	14