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 |
|
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 |
|
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 | 26.1 |
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) |
|
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. |
|
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 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 patient-reported symptoms and health-related quality of life
of patients receiving BNT113 in combination with patients receiving
pembrolizumab compared to pembrolizumab monotherapy. |
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 BICR and by investigator's 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 investigator's 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 the anti-tumor activity of BNT113 in combination with
pembrolizumab compared to pembrolizumab monotherapy according to
RECIST 1.1 assessed by BICR. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must sign the written ICF 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.
5. Patients who have a tumor that expresses PD-L1 [CPS ≥1] as
determined by the approved test PD-L1 IHC 22C3 pharmDx kit
performed and evaluated according to the manufacturer's specifications
and relevant regulatory approvals.
6. The eligible primary tumor locations are oropharynx, oral cavity,
hypopharynx, and larynx.
7. 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.
8. Patients who have measurable disease based on RECIST 1.1 as
determined by the site and confirmed by blinded independent central
review (BICR). Tumor lesions situated in a previously irradiated area
may be considered measurable if progression has been demonstrated in
such lesions 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 described in the protocol.
11. Patients have adequate hepatic function, as defined in the protocol.
12. Patients should have adequate kidney function, assessed by the
estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 using
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
equation.
13. Patients should be stable with adequate coagulation, as determined
by the investigator. Results should be discussed with the Medical
Monitor if:
a. international normalized ratio (INR) or prothrombin time (PT) >1.5 ×
ULN (unless on therapeutic anticoagulants with values within
therapeutic window),
b. activated partial thromboplastin time (aPTT) >1.5 × ULN (unless on
therapeutic anticoagulants with values within therapeutic window).
14. All patients must provide a tumor tissue sample (FFPE blocks or both
slides and curls) from archival tissue, or fresh biopsy if a biopsy is
performed as part of the patient's standard clinical practice before the
first dose of trial treatment. The sample should be preferably derived
from a current site of metastatic or recurrent disease. Otherwise, a
sample from the primary tumor can be submitted. 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.
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 6 months 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 6 months 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 6 months after
receiving the last dose of BNT113 AND for at least 6 months after
receiving the last dose of pembrolizumab. Additionally, patients are
required to use double barrier contraception defined as a condom with
spermicidal jelly, foam, suppository or film, together with the highly
effective contraception method. Male patients must also agree not to
donate sperm during the trial and for 6 months after receiving the last
dose of BNT113 AND for at least 6 months after receiving the last dose of
pembrolizumab.
Female partners of male patients should use a highly effective method of
contraception. |
|
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 infection.
c. Hepatitis C (unless considered cured)
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 1: Adjuvant hormone therapy used for breast cancer in long-term
remission is allowed.
Note 2: 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 treatment with anti-cancer immunomodulating agents, such as
blockers of PD 1, PD-L1, tumor necrosis factor receptor superfamily
member 9 (TNFRSF9, 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.
12. Treatment with non-systemic anti-cancer therapy (e.g., radiotherapy
or surgery) within 2 weeks prior to randomization.
Note: Prior treatment with bone resorptive therapy, such as
bisphosphonates (e.g., pamidronate, zoledronic acid) and denosumab, is
allowed.
13. 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.
14. 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 no evidence of clinical or radiological progression within 4 wks
before signing the informed consent,
d. do not require steroid therapy within 7 d before randomization or are
undergoing slow steroid tapering, currently at doses ≤10 mg and
neurologically stable.
e. spinal bone metastases are allowed unless imminent fracture or cord
compression is anticipated.
15. Patients who have previously been enrolled in this trial (rescreening
is allowed once).
16. 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.
17. 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 IRB.
18. Patients that have disease suitable for local therapy administered
with curative intent.
19. Patients that have a life expectancy of less than 3 months and/or
have rapidly progressive disease, as assessed by the treating
investigator.
20. 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. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Safety Run-In Phase (Part A):
Occurrence of TEAEs 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) |
|
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)
- Duration of Response (DoR)
- Occurrence of TEAEs |
|
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. |
|
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 | 4 |
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 |
Chile |
Singapore |
Taiwan |
Australia |
Brazil |
Canada |
Israel |
Korea, Republic of |
Mexico |
Russian Federation |
United Kingdom |
United States |
Austria |
Czechia |
Denmark |
France |
Germany |
Hungary |
Italy |
Poland |
Portugal |
Slovakia |
Spain |
Sweden |
Türkiye |
|
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.
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. |
|
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 | 9 |
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 |