An open-label Phase II/III randomized trial of BNT113 in combination with pembrolizumab versus pembrolizumab monotherapy as a first line therapy in patients with unresectable recurrent, or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) which is positive for human papilloma virus 16 (HPV16+) and expresses PD-L1

Trial ID: 2024-512671-12-00
Protocol: BNT113-01
Sponsor: BioNTech SE

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Diseases & Conditions

Squamous cell carcinoma of head and neck

Objectives

The primary objective of the safety run-in phase (Part A) is to assess the safety and tolerability profile of BNT113 in combination with pembrolizumab. The primary objective of the randomized phase (Part B) is to demonstrate superiority of BNT113 in combination with pembrolizumab compared with pembrolizumab monotherapy in terms of improved overall survival (OS). Additionally, Part B aims to evaluate the efficacy of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy in terms of progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by blinded independent central review (BICR). These primary objectives are clinically relevant for determining whether the addition of BNT113 to pembrolizumab provides meaningful therapeutic benefit in terms of survival outcomes for patients with unresectable recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that is positive for human papilloma virus 16 (HPV16+) and expresses PD-L1.

The secondary objectives include: • Safety run-in phase (Part A): To assess the anti-tumor activity of BNT113 in combination with pembrolizumab according to RECIST 1.1 assessed by BICR and by investigator's assessment respectively. • Randomized phase (Part B): To assess the anti-tumor activity of BNT113 in combination with pembrolizumab compared with pembrolizumab monotherapy according to RECIST 1.1 by investigator's assessment. • Randomized phase (Part B): To evaluate the efficacy of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy in terms of progression-free survival (PFS) rate according to RECIST 1.1 assessed by BICR. • Randomized phase (Part B): To assess the anti-tumor activity of BNT113 in combination with pembrolizumab compared with pembrolizumab monotherapy according to RECIST 1.1 assessed by BICR. • Randomized phase (Part B): To assess the safety and tolerability profile of BNT113 in combination with pembrolizumab compared with pembrolizumab monotherapy. • Randomized phase (Part B): To evaluate the efficacy of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy in terms of progression-free survival (PFS) according to RECIST 1.1 by investigator's assessment.

Participants

This clinical trial enrolled a total of **252 participants** diagnosed with **unresectable**, **metastatic**, or **recurrent head and neck squamous cell carcinoma**. The study population included both **male and female patients** aged **18 years and older**. Participants were required to have histologically confirmed **HPV16-positive** disease affecting the **oropharynx**, **oral cavity**, **hypopharynx**, or **larynx**, with tumors expressing **PD-L1** at a combined positive score of 1 or greater. All enrolled patients presented with disease considered incurable by local therapies and had **measurable disease** according to RECIST 1.1 criteria. Participants were required to have an **Eastern Cooperative Oncology Group performance status** of 0 or 1, indicating relatively preserved functional capacity. Key eligibility requirements included adequate **bone marrow function**, **hepatic function**, **renal function** with an estimated glomerular filtration rate of at least 30 mL/min/1.73m², and stable coagulation parameters. Patients who had received prior systemic anticancer therapy in the incurable recurrent or metastatic setting were excluded, though prior systemic therapy completed more than 6 months before enrollment as part of multimodal treatment for locally advanced disease was permitted. Women of childbearing potential and sexually active male participants were required to use highly effective contraception methods. The trial included a vulnerable population as designated in the study design.

Plans and Procedures

This is an open-label, **randomized**, **Phase II/III** clinical trial evaluating **BNT113** in combination with **pembrolizumab** versus pembrolizumab **monotherapy** as first-line treatment in patients with **unresectable recurrent or metastatic head and neck squamous cell carcinoma** that is positive for **human papilloma virus 16** (HPV16+) and expresses **PD-L1**. The trial consists of two parts: a safety run-in phase (Part A) and a randomized phase (Part B). Part A assesses the safety and tolerability profile of BNT113 in combination with pembrolizumab. Part B aims to demonstrate superiority of the combination therapy compared with pembrolizumab monotherapy in terms of improved **overall survival** (OS). The trial will also evaluate **progression-free survival** (PFS) according to **RECIST 1.1** as assessed by **blinded independent central review** (BICR). The estimated recruitment start date is July 2021, with an estimated end date in May 2026.

Eligible patients must be aged 18 years or older and have histologically confirmed recurrent or metastatic HPV16+ head and neck squamous cell carcinoma that is considered incurable by local therapies. The eligible primary tumor locations include **oropharynx**, **oral cavity**, **hypopharynx**, and **larynx**. Patients must have tumors that express PD-L1 with a **combined positive score** (CPS) ≥1 as determined by the CE-marked/FDA-approved CDx PD-L1 IHC 22C3 pharmDx. Patients must have **measurable disease** based on RECIST 1.1 and an **Eastern Cooperative Oncology Group** (ECOG) **performance status** ≤1. Patients must not have received prior systemic anticancer therapy in the incurable recurrent or metastatic setting, although systemic therapy completed more than 6 months prior to randomization as part of multimodal treatment for locally advanced disease is permitted. Adequate bone marrow, hepatic, and kidney function is required, with **estimated glomerular filtration rate** (eGFR) ≥30 mL/min/1.73m² using the **Chronic Kidney Disease Epidemiology Collaboration** (CKD-EPI) equation. Patients must provide a tumor tissue sample from archival tissue or a fresh biopsy sample if performed as part of standard clinical practice before the first dose of trial treatment.

BNT113 is administered as a concentrate for dispersion for **injection** via **intravenous use**, with a maximum daily dose of 100 µg and a maximum total dose of 3950 µg over a maximum treatment period of 25 weeks. Pembrolizumab is administered via **intravenous infusion**, with a maximum daily dose of 200 mg and a maximum total dose of 7000 mg over a maximum treatment period of 24 months. The primary endpoints for Part A include the occurrence of **treatment-emergent adverse events** (TEAEs) assessed according to **Common Terminology Criteria for Adverse Events version 5.0** (CTCAE v5.0), including Grade ≥3, serious, and fatal TEAEs by relationship. For Part B, the primary endpoints are overall survival defined as the time from randomization to death from any cause, and progression-free survival defined as the time from randomization to the first objective tumor progression per RECIST 1.1 assessed by BICR or death from any cause, whichever occurs first.

Secondary endpoints for Part A include **overall response rate** (ORR) defined as the proportion of patients with a **complete response** (CR) or **partial response** (PR) as best overall response, **duration of response** (DoR) defined as the time from first objective response to first occurrence of objective tumor progression or death, and **disease control rate** (DCR) defined as the proportion of patients with CR, PR, or **stable disease** (SD) as best overall response. Secondary endpoints for Part B include ORR per RECIST 1.1 assessed by BICR and by investigator's assessment, PFS by investigator's assessment, PFS rates at 6 and 12 months, duration of response, and the occurrence of TEAEs including dose reduction, delay, and discontinuation of trial treatments due to TEAEs. Patients are required to sign written **informed consent** before any screening procedure. Women of childbearing potential, male patients who are sexually active with women of childbearing potential, and female partners of male patients must use a highly effective method of **contraception** up to at least 6 months after receiving the last dose of trial treatment and agree not to donate eggs or sperm. The expected length of participant involvement varies depending on treatment response and tolerability, with a maximum treatment period of up to 25 weeks for BNT113 and up to 24 months for pembrolizumab. Conditions that may lead to early termination from the study include the occurrence of unacceptable toxicity, disease progression, withdrawal of consent, or investigator decision.

Treatment

The experimental treatment consists of **BNT113**, a concentrate for dispersion for injection containing two active substances of nucleic acid origin: **RBL015.2** and **RBL016.2**. BNT113 is administered via **intravenous use** with a maximum daily dose of 100 micrograms. The maximum total dose over the treatment period is 3950 micrograms, administered over a maximum treatment period of 25 weeks. BNT113 is provided by BioNTech SE and is also known by the alternative designation RBL015.1 and RBL016.1. This investigational medicinal product serves as the test treatment in the clinical trial.

**Pembrolizumab** is used as both a combination partner with BNT113 and as a comparator treatment in the monotherapy arm. Pembrolizumab is a protein-based active substance administered via **intravenous infusion**. The maximum daily dose of pembrolizumab is 200 milligrams, with a maximum total dose of 7000 milligrams over the treatment period. The maximum treatment period for pembrolizumab is 24 weeks. Pembrolizumab is classified under **ATC code L01FF02** and is also known by several synonyms including Lambrolizumab, MK-3475, SCH-900475, BAT3306, Pabolizumab, FYB206, and ABP 234. This medicinal product serves as the test treatment when combined with BNT113 and as the active comparator in the monotherapy arm.

The trial follows an open-label design with two distinct phases. The safety run-in phase (Part A) evaluates the safety and tolerability profile of BNT113 in combination with pembrolizumab. The randomized phase (Part B) compares BNT113 in combination with pembrolizumab against pembrolizumab monotherapy in patients with unresectable recurrent or metastatic **head and neck squamous cell carcinoma** that is positive for **human papilloma virus 16** and expresses **PD-L1**. Both investigational products are designated for use in this specific patient population as first-line therapy.

Efficacy

Efficacy will be assessed through multiple parameters across the safety run-in phase and the randomized phase of the trial. In the safety run-in phase (Part A), efficacy evaluation includes overall response rate (ORR), defined as the proportion of patients achieving complete response or partial response as best overall response, duration of response (DoR), measured from the time of first objective response to the first occurrence of objective tumor progression or death from any cause, and disease control rate (DCR), defined as the proportion of patients with complete response, partial response, or stable disease as best overall response.

In the randomized phase (Part B), the primary efficacy endpoints include overall survival (OS), defined as the time from randomization to death from any cause, and progression-free survival (PFS), defined as the time from randomization to the first objective tumor progression per RECIST 1.1 assessed by blinded independent central review (BICR) or death from any cause, whichever occurs first. Secondary efficacy endpoints in Part B include overall response rate defined as the proportion of patients with complete response or partial response per RECIST 1.1 assessed by BICR as best overall response, progression-free survival per RECIST 1.1 by investigator's assessment, objective response rate per RECIST 1.1 by investigator's assessment, PFS rate at 6 months and 12 months defined as the proportion of patients without objective tumor progression per RECIST 1.1 assessed by BICR or death from any cause at these timepoints, PFS rate at 6 months and 12 months per RECIST 1.1 by investigator's assessment, and duration of response defined as the time from first objective response per RECIST 1.1 assessed by BICR to first occurrence of objective tumor progression assessed by BICR or death from any cause, whichever occurs first.

Tumor assessments will be performed according to RECIST 1.1 criteria utilizing both blinded independent central review and investigator's assessment. Safety assessments include the occurrence of treatment-emergent adverse events according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), including Grade ≥3, serious, and fatal treatment-emergent adverse events by relationship, as well as occurrence of dose reduction, delay, and discontinuation of trial treatments due to treatment-emergent adverse events.

Inclusion and Exclusion Criteria

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Inclusion Criteria

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 with 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 CE-marked/FDA-approved CDx PD-L1 IHC 22C3 pharmDx performed according to the manufacturer’s instructions for use.
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 are considered measurable, if progression has been demonstrated in such lesions 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/min/1.73m² using the Chronic Kidney Disease Epidemiology Collaboration (CKD-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. Alternatively, a fresh biopsy sample could be provided 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.

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Exclusion Criteria

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 prior to treatment if fully recovered, 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.
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 adverse events (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.
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.
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, dry mouth, or any sequelae from previous treatments may be eligible at investigator's discretion if the conditions are stable and adequately managed (e.g., stable medication) and pose no further medical risk to the patient.
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.
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.
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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	14 Jul 2021	5
Belgium	Recruiting	14 Jul 2021	4
Czechia	Recruiting	14 Jul 2021	3
France	Recruiting	14 Jul 2021	24
Germany	Recruiting	14 Jul 2021	22
Hungary	Recruiting	14 Jul 2021	1
Italy	Recruiting	14 Jul 2021	17
Poland	Recruiting	14 Jul 2021	10
Portugal	Recruiting	14 Jul 2021	3
Spain	Recruiting	14 Jul 2021	7