| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable recurrent, or metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) which is positive for human papilloma virus 16 (HPV16+) and expresses PD-L1 |
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| E.1.1.1 | Medical condition in easily understood language |
| Head and neck cancer positive for human papilloma virus 16 and expressing the protein PD-L1 |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Safety Run-In Phase (Part A):
- To assess the safety and tolerability profile of BNT113 in combination with pembrolizumab.
Randomized Phase (Part B):
- To demonstrate superiority of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy in terms of improved OS.
- To assess the anti-tumor activity of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy according to RECIST 1.1 assessed by BICR.
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| E.2.2 | Secondary objectives of the trial |
Safety Run-In Phase (Part A):
- To assess the anti-tumor activity of BNT113 in combination with pembrolizumab according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by blinded independent central review (BICR) and by investigators assessment respectively.
Randomized Phase (Part B):
- To assess the anti-tumor activity of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy according to RECIST 1.1 by investigators assessment.
- To evaluate the efficacy of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy in terms of PFS according to RECIST 1.1.
- To assess the safety and tolerability profile of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy.
- To assess health-related quality of life of BNT113 in combination with pembrolizumab compared to pembrolizumab monotherapy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 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.
2. Patients must be aged ≥18 years on the date of signing the informed consent.
3. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the trial.
4. Patients who present histologically confirmed recurrent or metastatic HPV16+ HNSCC that is considered incurable by local therapies.
• Note 1: HPV16 positivity in the Safety Run-In Phase (Part A) will be determined using an investigational real time PCR-based (qPCR) test detecting HPV16 E7 DNA derived from FFPE tumor tissue (therascreen HPV RGQ PCR Kit)
• Note 2: For the randomized phase (Part B), HPV16 positivity will be determined using an investigational real time PCR-based qPCR test (therascreen HPV Panel RGQ PCR Kit) detecting HPV16 E7 DNA derived from FFPE tumor tissue.
5. Patients who have a tumor expressing PD-L1 [CPS ≥1] as determined by the FDA-approved test PD L1 22C3 pharmDx kit performed and evaluated according to the manufacturer’s specifications.
6. The eligible primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. Patients may not have a primary tumor site of nasopharynx (any histology).
7. Patients must not have had prior systemic anticancer therapy administered in the 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.
8. 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 disease by RECIST 1.1.
9. Patients have Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
10. Patients have adequate bone marrow function as defined by hematological parameters as described in protocol points a/b/c.
11. Patients have adequate hepatic function, as defined in protocol points a/b.
12. Patients should have adequate kidney function, assessed by the estimated glomerular filtration rate ≥45 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CPK-EPI) equation Kidney Disease Improving Global Outcomes [KDIGO] 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease; Levey et al. 2009).
13. Patients should be stable with adequate coagulation, as defined in the protocol points a/b.
14. All patients must provide a tumor tissue sample (FFPE blocks/slides) from archival tissue, or fresh biopsy if collected as part of patient’s standard clinical practice before the first dose of trial treatment. The sample should preferably be derived from the primary tumor and from the last tumor sample taken. FFPE block is preferred. If not possible, at least 16 (preferably 20) consecutive slides should be provided. More information about sample quality, requirements, and handling will be provided in a Laboratory Manual.
15. Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin) at screening. Patients that are postmenopausal or permanently sterilized can be considered as not having reproductive potential.
16. WOCBP must agree to practice at least one highly effective method of contraception during trial, i.e., starting at screening, during the trial and for at least 90 d after receiving the last dose of BNT113 AND for at least 6 months after receiving the last dose of pembrolizumab.
17. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial starting at screening, during the trial and for 90 d after receiving the last dose of BNT113 AND for at least 6 months after receiving the last dose of pembrolizumab.
18. A man who is sexually active with a WOCBP and has not had a vasectomy must agree to practice at least one highly effective contraception method during the trial and for at least 90 d after receiving the last dose of BNT113 AND for at least 6 months after receiving the last dose of pembrolizumab.
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| E.4 | Principal exclusion criteria |
1. Patients are pregnant or breastfeeding.
2. Patients present primary tumor site of nasopharynx (any histology).
3. Patients with uncontrolled intercurrent illness as defined in the protocol points a/b/c/d/e/f/ g/h/I/j/k/l/m.
4. Patients with a known allergy, hypersensitivity, or intolerance to BNT113 or its excipients, or to pembrolizumab or its excipients.
5. Patients who have had a splenectomy.
6. Patients who have had major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, or have not fully recovered from surgery, or have a surgery planned during the time of trial participation.
7. Patients who have a known history (testing not required) or has a positive test at screening of any of the following:
a. Human immunodeficiency virus (HIV) 1 or 2.
b. Hepatitis B (carrier or active infection).
c. Hepatitis C (unless considered cured 5 years post curative anti-viral therapy).
8. 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).
Note: Any uncertainties should be discussed with the Medical Monitor.
9. 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.
10. Patients who have received or currently receive the therapy/medication as defined in the protocol points a/b/c/d/e/f.
11. Prior anti-cancer therapy in the metastatic or in the unresectable recurrent HNSCC setting.
12. Prior treatment with anti-cancer immunomodulating agents, such as blockers of 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 before the first dose of BNT113.
13. Treatment with other anti-cancer therapy including chemotherapy, radiotherapy with curative intent, major surgery with curative intent or biological cancer therapy within 6 months prior to randomization. Adjuvant hormone therapy used for breast cancer in long term remission (refer to Exclusion criterion#8) is allowed.
Note 1: Palliative radiotherapy and palliative surgery are allowed.
Note 2: Prior treatment with bone resorptive therapy, such as bisphosphonates (e.g., pamidronate, zoledronic acid) and denosumab, is allowed assuming that the patients have been on stable doses for ≥4 weeks prior to first dose of trial treatment.
14. Current evidence of Common Terminology Criteria for Adverse Events (CTCAE, version 5.0) 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 may be eligible at Investigator’s discretion.
15. Current evidence of new or growing brain or spinal metastases during screening. Patients with known brain or spinal metastases may be eligible if they:
a. had radiotherapy or another appropriate therapy for the brain or spinal metastases,
b. have no neurological symptoms (excluding Grade ≤2 neuropathy),
c. have stable brain or spinal disease on the computer tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the informed consent,
d. do not require steroid therapy within 7 d before randomization,
e. spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated.
16. Patients who have previously been enrolled in this trial.
17. Patients with substance abuse or known medical, psychological, or social conditions that may interfere with the patient’s participation in the trial or evaluation of the trial results.
18. 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).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Run-In Phase (Part A):
Occurrence of treatment-emergent adverse event (TEAE) assessed according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) including Grade ≥3, serious, fatal TEAE by relationship
Randomized Phase (Part B):
- Overall Survival (OS) defined as the time from randomization to death from any cause.
- Overall response rate (ORR)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AEs and SAEs: Monitored from signing of the ICF until Safety Follow-Up 2 (SFU2)
Overall Survival (OS): Time from randomization to death from any cause |
|
| E.5.2 | Secondary end point(s) |
Safety Run-In Phase (Part A):
- Overall response rate (ORR)
- Duration of Response (DoR)
- Disease control rate (DCR)
Randomized Phase (Part B):
- Overall response rate (ORR)
- Progression-Free Survival (PFS)
- Disease control rate (DCR)
- Duration of Response (DoR)
- Occurrence of TEAEs
- Patient-reported outcome (PRO) scores |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Tumor Evaluation: Assessed every 9 (±1) wks for the first 6 months, and then every 12 (±2) wks regardless of any dose delays, until disease progression or until the start of next-line anti-cancer therapy
DOR: Time from first objective response (CR or PR) to first occurrence of objective tumor progression, or death from any cause, whichever occurs first
PFS: Time from randomization to first objective tumor progression, or death from any cause, whichever occurs first.
DCR: Assessed at least 6 weeks after first dose
PRO/QoL assessments: At screening, Start of every cycle till EOT |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Biomarker Analysis, Immunogenicity |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Different dose of the same product |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Mexico |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
A patient is considered to have completed the trial if he/she has completed all phases of the trial including survival follow up.
The end of the trial will be declared at the time at which:
• all patients have discontinued trial treatment; and
• all patients have completed the visit Safety Follow-Up 2 (SFU2); and
• the primary and secondary analyses can be performed (i.e., at least 201 OS events have been occurred).
or
• the sponsor discontinues the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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