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

Sponsor

Nykode Therapeutics ASA (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06016920

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Location

Arms

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
HPV-Related Squamous Cell Carcinoma HNSCC	Biological: VB10.16 Drug: Pembrolizumab	Phase 1/Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

51 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention 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 dosesDose-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)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

Sep 1, 2027

Anticipated Study Completion Date :

Jan 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase1: Dose Escalation: 3 mg VB10.16 + Pembrolizumab 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 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. Drug: Pembrolizumab 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. Other Names: KEYTRUDA
Experimental: Phase 1: Dose Escalation: 6 mg VB10.16 + Pembrolizumab 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 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. Drug: Pembrolizumab 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. Other Names: KEYTRUDA
Experimental: Phase 1: Dose Escalation: 9 mg VB10.16 + Pembrolizumab 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 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. Drug: Pembrolizumab 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. Other Names: KEYTRUDA
Experimental: Phase 2: Dose Expansion: High dose of VB10.16 + Pembrolizumab 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 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. Drug: Pembrolizumab 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. Other Names: KEYTRUDA
Experimental: Phase 2: Dose Expansion: 3 mg VB10.16 + Pembrolizumab 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 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. Drug: Pembrolizumab 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. Other Names: KEYTRUDA

Outcome Measures

Primary Outcome Measures

Phase 1: Dose Escalation: Dose Limiting Toxicities (DLT) [42 days]
Proportion of patient with Dose Limiting Toxicities (DLTs).
Phase 2: Dose Expansion: AEs [50 Weeks]
Proportion of patients with AEs following treatment initiation by severity grade.
Phase 2: Dose Expansion: Discontinuation due to adverse reaction [50 weeks]
Proportion of patients who discontinue due to an adverse reaction.
Phase 2: Dose Expansion: Objective Response Rate (ORR) [50 weeks]
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.
Phase 2: Dose Expansion: Immune response [50 weeks]
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.
Phase 1+2: Full trial: Objective Response Rate (ORR) [50 weeks]
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.
Phase 1+2: Full trial: Objective Response Rate (ORR) [103 weeks]
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.
Phase 1+2: Full trial: Duration of response (DOR) [50 weeks]
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.
Phase 1+2: Full trial: Duration of response (DOR) [103 weeks]
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.
Phase 1+2: Full trial: Progression-free survival (PFS) [50 weeks]
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.
Phase 1+2: Full trial: Progression-free survival (PFS) [103 weeks]
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.
Phase 1+2: Full trial: Proportion Progression-free [50 weeks]
Proportion of patients who progression-free and alive.
Phase 1+2: Full trial: Proportion Progression-free [103 weeks]
Proportion of patients who are progression-free and alive.
Phase 1 + 2: Full trial: Overall survival (OS) [50 weeks]
Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause.
Phase 1 + 2: Full trial: Overall survival (OS) [103 weeks]
Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause.
Phase 1 + 2: Full trial: Proportion alive [50 weeks]
Proportion of patients who are alive.
Phase 1 + 2: Full trial: Proportion alive [103 weeks]
Proportion of patients who are alive.

Secondary Outcome Measures

Phase 2: Dose Expansion: Disease control rate (DCR) [50 weeks]
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.
Phase 2: Dose Expansion: Duration of response (DOR) [50 weeks]
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.
Phase 2: Dose Expansion: Duration of complete response (DOCR) [50 weeks]
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.
Phase 2: Dose Expansion: Duration of Disease Control (DODC) [50 weeks]
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.
Phase 2: Dose Expansion: Time to Response (TTR) [50 weeks]
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.
Phase 2: Dose Expansion: Progression-free survival (PFS) [50 weeks]
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.
Phase 2: Dose Expansion: Overall Survival (OS) [50 weeks]
Overall survival (OS), defined as the time from VB10.16 treatment start date to the date of death from any cause.
Phase 2: Proportion of progression-free [26 weeks]
Proportion of patients who are progression-free and alive.
Phase 2: Proportion of progression-free [50 weeks]
Proportion of patients who are progression-free and alive.
Phase 2: Patients alive [26 weeks]
Proportion of patients who are alive.
Phase 2: Patients alive [50 weeks]
Proportion of patients who are alive.
Phase 1+2: Full trial: AEs following treatment initiation [50 weeks]
Proportion of patients with AEs following treatment initiation by severity grade.
Phase 1+2: Full trial: AEs following treatment initiation [103 weeks]
Proportion of patients with AEs following treatment initiation by severity grade.
Phase 1+2: Discontinuation due to an adverse reaction [50 weeks]
Proportion of patients who discontinue due to an adverse reaction.
Phase 1+2: Discontinuation due to an adverse reaction [103 weeks]
Proportion of patients who discontinue due to an adverse reaction.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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