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

Study Overview
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Brief Summary
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This is a multi-center study in patients with un-resectable Recurrent or Metastatic HPV16-positive 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: a phase 1, dose escalation part, testing 3 different doses of VB10.16 in combination with a standard fixed dose of pembrolizumab. The goal of this part 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. In the second part of the trial, a phase 2a, dose expansion part, participants will receive either the highest safe dose of VB10.16 from part 1 or the 3 mg dose both in combination with pembrolizumab. The dose given to each participant will be decided in random. The trial is designed to define the optimal dose of VB10.16 in combination with pembrolizumab for future clinical studies based on the safety, tolerability and anti-tumor effect data generated.

Detailed Description
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This phase 1/2a, open-label, dose-finding trial is designed to evaluate the safety, tolerability, immunogenicity, and anti-tumor activity of VB10.16 immunotherapy in patients with HPV16-positive R/M HNSCC whose tumors express PDL1 (CPS ≥ 1) and who are eligible for pembrolizumab monotherapy as standard of care. The trial is designed to determine the biological optimal dose (BOD) of VB10.16 in combination with a fixed dose of pembrolizumab based on the totality of data (i.e., safety, tolerability, anti-tumor activity, and HPV16 E6/E7specific cellular immune response). The trial consists of 2 consecutive phases with separate patient groups in a seamless trial design: a dose escalation phase (phase 1) and a dose expansion phase (phase 2a). After completing 48 weeks of combination treatment, patients can either continue pembrolizumab treatment with 200 mg Q3W administration or change to 400 mg Q6W administration at the discretion of the investigator and after consultation with the Sponsor.

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

Conditions
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HPV-Related Squamous Cell Carcinoma, HNSCC

Intervention / Treatment
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* Biological: VB10.16
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: GENERAL REQUIREMENTS ≥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 considered incurable by local therapy and eligible for monotherapy with pembrolizumab HPV16 positivity of R/M HNSCC confirmed by designated central laboratory PD-L1 positivity (CPS ≥1) Must provide a tumor tissue sample collected prior to VB10.16 treatment initiation for baseline tumor microenvironment analyses Primary tumor location in the oropharynx, oral cavity, hypopharynx, or larynx At least 1 measurable lesion per RECIST 1.1 ORGAN FUNCTION Overall function: Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 Hematological function: Platelets 100 - 400 × 10^9/L (100,000 - 400,000/µL) Neutrophils (absolute neutrophil count [ANC]) ≥1.5 × 10^9/L (1,500/µL) Hemoglobin ≥5.6 mmol/L (9.0 g/dL) Hepatic and hemostatic function: Bilirubin (BILI), total ≤1.5 × upper limit of normal (ULN) (except Gilbert syndrome, then direct BILI ≤2 × ULN) Aspartate transaminase (AST) ≤ 2.5 × ULN Alanine transaminase (ALT) ≤ 2.5 × ULN Alkaline phosphatase ≤ 2.5 × ULN International normalized ratio (INR) ≤1.5 × ULN Renal function: Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m^2 using the Cockroft-Gault formula OTHER TRIAL REQUIREMENTS Female patients of childbearing potential: negative serum pregnancy test (≤72 hours) Female patients of childbearing potential and male patients must agree to use highly effective contraception, and male patients must refrain from sperm donation throughout the trial (14 days prior to initiation of treatment for oral contraception), and for at least 120 days (according to the latest country-specific pembrolizumab label) after the last dose of pembrolizumab and up to 6 months after the last dose of VB10.16, whichever comes last Patients capable of giving informed consent must provide signed and dated written informed consent prior to initiation of any study-related procedures. 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 systemic treatment for locoregionally advanced R/M HNSCC Primary tumor site of the 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 radiotherapy within 2 weeks of start of trial treatment or has had a 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 molecule 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 VB10.16 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) or an average cumulative dose of >140 mg prednisone (or dose equivalent) within the last 14 consecutive days prior to VB10.16 treatment start Administration of G-CSF/GM-CSF or transfusions with red blood cells, platelets, or plasma components ≤2 weeks prior to VB10.16 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) Has received prior surgery or prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment Any planned major surgery PRIOR OR CONCURRENT MORBIDITY Malignancy: Past or current malignancy other than inclusion diagnosis, except for: Cervical carcinoma, stage 1B or less Noninvasive basal cell or squamous cell skin carcinoma Noninvasive, superficial bladder cancer Prostate cancer with a current prostate-specific antigen level <0.1 ng/mL Any curable cancer with a complete response of >2 years' duration Hepatic and hemostatic function: Any current bleeding disorder, active bleeding, or bleeding diathesis Cardiovascular function: 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 VB10.16 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 Pulmonary function: Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease Immune system and infectious diseases: 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. No HIV testing is required unless mandated by a local health authority 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 drug excipients, or aminoglycosides (especially kanamycin). Central nervous system (CNS) function: 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 New (≤6 months), progressive and/or symptomatic brain metastases OTHER Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior 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 the patient's 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose-finding trial, including a dose escalation phase (phase 1) where participants are allocated sequentially to one of the 3 escalating doses; and a dose expansion phase (phase 2a) where participants are randomized to one of two doses
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase1: Dose Escalation: 3 mg VB10.16 + Pembrolizumab<br>3 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles Pembrolizumab will be given as standard of care/ background medication via i.v. infusions | Biological: VB10.16<br>* Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) starting at Week 1/Day 1 during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 48. A total of up to 10 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.<br>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg intravenous (i.v.) will be given in accordance with the local regulatory-approved label Q3W starting at Week 1/Day 1 for as long as the patient tolerates and continues to have clinical benefit from the treatment based on the patient and investigator's decision, up to a maximum of 35 treatments corresponding to approximately 2 years of treatment. After 48 weeks of treatment patients can continue on 200 mg Q3W or change to 400 mg Q6W at the discretion of the investigator and after consultation with the sponsor. Pembrolizumab will be given by i.v. infusion over 30 minutes.<br>* Other names: KEYTRUDA;|
| Experimental: Phase 1: Dose Escalation: 6 mg VB10.16 + Pembrolizumab<br>6 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles and quadriceps or gluteus muscles Pembrolizumab will be given as standard of care/ background medication via i.v. infusions | Biological: VB10.16<br>* Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) starting at Week 1/Day 1 during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 48. A total of up to 10 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.<br>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg intravenous (i.v.) will be given in accordance with the local regulatory-approved label Q3W starting at Week 1/Day 1 for as long as the patient tolerates and continues to have clinical benefit from the treatment based on the patient and investigator's decision, up to a maximum of 35 treatments corresponding to approximately 2 years of treatment. After 48 weeks of treatment patients can continue on 200 mg Q3W or change to 400 mg Q6W at the discretion of the investigator and after consultation with the sponsor. Pembrolizumab will be given by i.v. infusion over 30 minutes.<br>* Other names: KEYTRUDA;|
| Experimental: Phase 1: Dose Escalation: 9 mg VB10.16 + Pembrolizumab<br>9 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles and quadriceps and/or gluteus muscle Pembrolizumab will be given as standard of care/ background medication via i.v. infusions | Biological: VB10.16<br>* Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) starting at Week 1/Day 1 during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 48. A total of up to 10 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.<br>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg intravenous (i.v.) will be given in accordance with the local regulatory-approved label Q3W starting at Week 1/Day 1 for as long as the patient tolerates and continues to have clinical benefit from the treatment based on the patient and investigator's decision, up to a maximum of 35 treatments corresponding to approximately 2 years of treatment. After 48 weeks of treatment patients can continue on 200 mg Q3W or change to 400 mg Q6W at the discretion of the investigator and after consultation with the sponsor. Pembrolizumab will be given by i.v. infusion over 30 minutes.<br>* Other names: KEYTRUDA;|
| Experimental: Phase 2: Dose Expansion: High dose of VB10.16 + Pembrolizumab<br>The highest dose of VB10.16 to be safety-cleared in the escalation phase will be given via i.m. needle-free injections in the deltoid muscles and quadriceps and/or gluteus muscle Pembrolizumab will be given as standard of care/ background medication via i.v. infusions | Biological: VB10.16<br>* Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) starting at Week 1/Day 1 during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 48. A total of up to 10 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.<br>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg intravenous (i.v.) will be given in accordance with the local regulatory-approved label Q3W starting at Week 1/Day 1 for as long as the patient tolerates and continues to have clinical benefit from the treatment based on the patient and investigator's decision, up to a maximum of 35 treatments corresponding to approximately 2 years of treatment. After 48 weeks of treatment patients can continue on 200 mg Q3W or change to 400 mg Q6W at the discretion of the investigator and after consultation with the sponsor. Pembrolizumab will be given by i.v. infusion over 30 minutes.<br>* Other names: KEYTRUDA;|
| Experimental: Phase 2: Dose Expansion: 3 mg VB10.16 + Pembrolizumab<br>3 mg of VB10.16 via i.m. needle-free injections in the deltoid muscles Pembrolizumab will be given as standard of care/ background medication via i.v. infusions | Biological: VB10.16<br>* Intramuscular (i.m.) administrations of VB10.16 every 3 weeks (Q3W) starting at Week 1/Day 1 during a 12-week induction period, followed by a maintenance period with administrations every 6 weeks (Q6W) from Week 13 until Week 48. A total of up to 10 i.m. administrations will be given. VB10.16 will be administered via Pharma Jet® Stratis 0.5 mL needle free injection system.<br>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg intravenous (i.v.) will be given in accordance with the local regulatory-approved label Q3W starting at Week 1/Day 1 for as long as the patient tolerates and continues to have clinical benefit from the treatment based on the patient and investigator's decision, up to a maximum of 35 treatments corresponding to approximately 2 years of treatment. After 48 weeks of treatment patients can continue on 200 mg Q3W or change to 400 mg Q6W at the discretion of the investigator and after consultation with the sponsor. Pembrolizumab will be given by i.v. infusion over 30 minutes.<br>* Other names: KEYTRUDA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Dose Escalation: Dose Limiting Toxicities (DLT) | Proportion of patient with Dose Limiting Toxicities (DLTs). | 42 days | 
| Phase 2: Dose Expansion: AEs | Proportion of patients with AEs following treatment initiation by severity grade. | 50 Weeks | 
| Phase 2: Dose Expansion: Discontinuation due to adverse reaction | Proportion of patients who discontinue due to an adverse reaction. | 50 weeks | 
| Phase 2: Dose Expansion: Objective Response Rate (ORR) | Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response per RECIST 1.1. | 50 weeks | 
| Phase 2: Dose Expansion: Immune response | Proportion of patients with increased HPV16 E6/E7-specific cellular immune responses from baseline as measured by E6/E7-IFN-γ ELISpot in post-vaccination samples. | 50 weeks | 
| Phase 1+2: Full trial: Objective Response Rate (ORR) | Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response (BOR) per RECIST 1.1. | 50 weeks | 
| Phase 1+2: Full trial: Objective Response Rate (ORR) | Objective Response Rate (ORR), defined as the proportion of patients who have either confirmed CR or confirmed PR as best overall response per RECIST 1.1. | 103 weeks | 
| Phase 1+2: Full trial: Duration of response (DOR) | Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause. | 50 weeks | 
| Phase 1+2: Full trial: Duration of response (DOR) | Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause. | 103 weeks | 
| Phase 1+2: Full trial: Progression-free survival (PFS) | Progression-free survival (PFS), defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first. | 50 weeks | 
| Phase 1+2: Full trial: Progression-free survival (PFS) | Progression-free survival (PFS), defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first. | 103 weeks | 
| Phase 1+2: Full trial: Proportion Progression-free | Proportion of patients who progression-free and alive. | 50 weeks | 
| Phase 1+2: Full trial: Proportion Progression-free | Proportion of patients who are progression-free and alive. | 103 weeks | 
| Phase 1 + 2: Full trial: Overall survival (OS) | Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause. | 50 weeks | 
| Phase 1 + 2: Full trial: Overall survival (OS) | Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause. | 103 weeks | 
| Phase 1 + 2: Full trial: Proportion alive | Proportion of patients who are alive. | 50 weeks | 
| Phase 1 + 2: Full trial: Proportion alive | Proportion of patients who are alive. | 103 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Dose Expansion: Disease control rate (DCR) | Disease control rate (DCR), defined as the proportion of patients who have either confirmed CR, confirmed PR, or SD as BOR according to RECIST 1.1. | 50 weeks | 
| Phase 2: Dose Expansion: Duration of response (DOR) | Duration of response (DOR), defined as time from the date of first documented response of CR or PR to the date of the first documented progression or death due to any cause. | 50 weeks | 
| Phase 2: Dose Expansion: Duration of complete response (DOCR) | Duration of complete response (DOCR), defined as time from the date of first documented response of CR to the date of the first documented progression or death due to any cause. | 50 weeks | 
| Phase 2: Dose Expansion: Duration of Disease Control (DODC) | Duration of Disease Control (DODC), defined as time from the date of first documented response of CR, PR or SD to the date of the first documented progression or death due to any cause. | 50 weeks | 
| Phase 2: Dose Expansion: Time to Response (TTR) | Time to Response (TTR), s defined as the time from VB10.16 treatment start date to the date of first documented response of either confirmed CR or confirmed PR. | 50 weeks | 
| Phase 2: Dose Expansion: Progression-free survival (PFS) | Progression-free survival (PFS), defined as the time from the VB10.16 treatment start date to the date of the first documented progression or death from any cause, whichever occurs first. | 50 weeks | 
| Phase 2: Dose Expansion: Overall Survival (OS) | Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause. | 50 weeks | 
| Phase 2: Proportion of progression-free | Proportion of patients who are progression-free and alive. | 26 weeks | 
| Phase 2: Proportion of progression-free | Proportion of patients who are progression-free and alive. | 50 weeks | 
| Phase 2: Patients alive | Proportion of patients who are alive. | 26 weeks | 
| Phase 2: Patients alive | Proportion of patients who are alive. | 50 weeks | 
| Phase 1+2: Full trial: AEs following treatment initiation | Proportion of patients with AEs following treatment initiation by severity grade. | 50 weeks | 
| Phase 1+2: Full trial: AEs following treatment initiation | Proportion of patients with AEs following treatment initiation by severity grade. | 103 weeks | 
| Phase 1+2: Discontinuation due to an adverse reaction | Proportion of patients who discontinue due to an adverse reaction. | 50 weeks | 
| Phase 1+2: Discontinuation due to an adverse reaction | Proportion of patients who discontinue due to an adverse reaction. | 103 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PD-L1, Unresectable, recurrent, metastatic, HPV16 positive