Therapeutic HPV vaccine trial +/- anti-CD40 in HPV-driven squamous cell carcinoma

ISRCTN	ISRCTN51789191
DOI	https://doi.org/10.1186/ISRCTN51789191
ClinicalTrials.gov (NCT)	NCT03418480
Clinical Trials Information System (CTIS)	2014-002061-30
Protocol serial number	30900
Sponsor	University Hospital Southampton NHS Foundation Trust
Funders	European Commission, BioNTech

Submission date: 02/11/2016
Registration date: 15/12/2016
Last edited: 30/09/2026

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-of-a-vaccine-for-cancers-who-tested-positive-to-the-human-papilloma-virus-hare-40

Contact information

Ms Karen Martin
Public

Southampton Clinical Trials Unit
Southampton General Hospital
MP131
Tremona Road
Southampton
SO16 6YD
United Kingdom

Phone	+44 (0)23 8120 5154
Email	HARE-40@soton.ac.uk; ctuadmin@soton.ac.uk

Study information

Primary study design	Interventional
Study design	Non-randomized interventional study
Secondary study design	Non randomised study
Scientific title	Therapeutic HPV vaccine (BNT113) trial in HPV16 driven carcinoma
Study acronym	HARE-40
Study objectives	The overall aim of this study is to establish a safe and tolerable dose of HPV mRNA vaccine and assess if there is evidence of clinical effect according to irRECIST 1.1.
Ethics approval(s)	Approved 18/07/2016, London - West London & GTAC Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 104 8098; westlondon.rec@hra.nhs.uk), ref: 16/LO/0567
Health condition(s) or problem(s) studied	HPV-driven squamous cell carcinoma
Intervention	Added 18/09/2026: HARE-40 is a Phase I/II vaccine dose escalation trial with two different arms. The vaccine (BNT113 ) will be intravenously administered. Arm 1A (Phase I) will perform intrapatient dose escalation in patients with previously treated HPV16+ Head & Neck Cancer using two dose cohorts to establish a safe, tolerable and recommended dose of BNT113. Arm 1A will consist of 6 patients in Cohort 1 and 9 patients in Cohort 2. Arm 1B (Phase I/II) will begin by performing intrapatient dose escalation in 15 patients with advanced HPV16+ cancer (head and neck, anogenital, penile, cervical or unknown primary) using a single cohort to establish a safe, tolerable and recommended dose of BNT113. Following DMEC review with input from SRC Arm 1B will be expanded to a second cohort of 14 patients to assess the Phase II clinical endpoints of activity and safety.
Intervention type	Biological/Vaccine
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	BNT113
Primary outcome measure(s)	Current primary outcomes as of 18/09/2026: Arms 1A and 1B: Determination of a suitable dose of BNT113 based on defined criteria for DLTs (dose limiting toxicities) according to CTCAE version 4.03. This is measured by evaluation of DLTs until 28 days after last study treatment. Arm 1B: Disease control rate, defined as the rate of complete response, partial response or stable disease, is measured according to irRECIST 1.1 at the end of treatment CT scan at Day 85. Previous primary outcomes: Arm 1A: The suitable dose of HPV mRNA vaccine is based on defined criteria for DLTs (dose limiting toxicities). This is measured by evaluation of DLTs until 28 days after last study treatment. Arm 1B: Disease control rate, defined as the rate of complete response, partial response or stable disease, is measured according to irRECIST 1.1 at the end of treatment CT scan at Day 85.
Key secondary outcome measure(s)	Current secondary outcomes as of 18/09/2026: Arm 1A: 1. Adverse event rate is measured according to CTCAE v4.03 at the end of the trial until 28 days after last study treatment 2. Systemic levels of induced HPV-16 specific T-cell and B-cell immune responses are measured using specific biomarker tests at the end of study treatment 3. Duration of detectable vaccine-induced immune response is measured using specifically designed immune-assays at the end of study treatment 4. The clinical and immunological evaluation of DTH sites is assessed prior to vaccination and after the vaccination course, by clinical assessment and tissue biopsy, 48 hours post DTH injection in patients who had DTH control reaction assessments. Arm 1B: 1. Adverse event rate is measured according to CTCAE v4.03 at the end of the trial until 28 days after last study treatment 2. Systemic levels of induced HPV-16 specific T-cell and B-cell immune responses are measured using specific biomarker tests during the course of trial at the end of study treatment 3. Duration of detectable vaccine-induced immune response is measured using specifically designed immune-assays, such as PBMCs during the course of the trial at the end of study treatment 4. The clinical and immunological evaluation of DTH sites is assessed prior to vaccination and after the vaccination course, by clinical assessment and tissue biopsy 48 hours post DTH injection in patients who had DTH control reaction assessment. 5. Percentage change in densities of immune cells in tumour tissue (where paired samples can be collected) is assessed using tumour tissue biopsies at baseline and follow-up (Day 85) 6. Numbers of immune cells is assessed by immunohistochemistry or flow cytometry at baseline and follow-up (Day 85) 7. Clinical response is measured according to irRECIST 1.1 at 85 days and 6 and 9 months 8. Disease control rate is measured according to irRECIST 1.1 at 6 and 9 months 9. Best overall response is measured according to irRECIST 1.1 at 9 months 10. Intra-tumoural levels of HPV16‐specific immune responses (where paired tumour samples can be collected) is measured using tumour tissue biopsies at baseline and follow-up (Day 85) 11. Safety/tolerability of HPV mRNA vaccine in terms of the adverse event rate is measured according to CTCAE v4.03 at 36 and 85 days 12. Grade 3 or above vaccine- or combination administration-related toxicity is measured within 90 days after the last administration of study drugs 13. Progression-Free Survival (PFS) is measured from baseline to date of disease progression or death, from any cause 14. Overall Survival (OS) is measured from baseline to date of disease progression or death, from any cause 15. Disease Specific Interval (DSI) is measured from baseline to date of disease progression or death, from any cause Previous secondary outcomes: Arm 1A: 1. Adverse event rate is measured according to CTCAE v4.03 at the end of the trial until 28 days after last study treatment 2. Systemic levels of induced HPV-16 specific T-cell and B-cell immune responses are measured using specific biomarker tests at the end of study treatment 3. Duration of detectable vaccine-induced immune response is measured using specifically designed immune-assays at the end of study treatment 4. The clinical and immunological evaluation of DTH sites is assessed prior to vaccination and after the vaccination course, by clinical assessment and tissue biopsy, 48 hours post DTH injection Arm 1B: 1. Adverse event rate is measured according to CTCAE v4.03 at the end of the trial until 28 days after last study treatment 2. Systemic levels of induced HPV-16 specific T-cell and B-cell immune responses are measured using specific biomarker tests during the course of trial at the end of study treatment 3. Duration of detectable vaccine-induced immune response is measured using specifically designed immune-assays, such as PBMCs during the course of the trial at the end of study treatment 4. The clinical and immunological evaluation of DTH sites is assessed prior to vaccination and after the vaccination course, by clinical assessment and tissue biopsy 48 hours post DTH injection 5. Percentage change in densities of immune cells in tumour tissue (where paired samples can be collected) is assessed using tumour tissue biopsies at baseline and follow-up (Day 85) 6. Numbers of immune cells is assessed by immunohistochemistry or flow cytometry at baseline and follow-up (Day 85) 7. Clinical response is measured according to irRECIST 1.1 at 85 days and 6 and 9 months 8. Disease control rate is measured according to irRECIST 1.1 at 6 and 9 months 9. Best overall response is measured according to irRECIST 1.1 at 9 months 10. Intra-tumoural levels of HPV16‐specific immune responses (where paired tumour samples can be collected) is measured using tumour tissue biopsies at baseline and follow-up (Day 85) 11. Safety/tolerability of HPV mRNA vaccine in terms of the adverse event rate is measured according to CTCAE v4.03 at 36 and 85 days 12. Grade 3 or above vaccine- or combination administration-related toxicity is measured within 90 days after the last administration of study drugs 13. Progression-Free Survival (PFS) is measured from baseline to date of disease progression or death, from any cause 14. Overall Survival (OS) is measured from baseline to date of disease progression or death, from any cause 15. Disease Specific Interval (DSI) is measured from baseline to date of disease progression or death, from any cause
Completion date	24/01/2024

Eligibility

Participant type(s)	Patient
Age group	Mixed
Lower age limit	18 Years
Upper age limit	110 Years
Sex	All
Target sample size at registration	44
Total final enrolment	30
Key inclusion criteria	Current inclusion criteria as of 18/09/2026: Inclusion Criteria Arm 1A: 1. Previous HPV16+ head and neck squamous cell carcinoma 2. At least 12 months after completion of treatment 3. Within 5 years of treatment completion 4. Currently no clinical evidence of disease 5. ECOG performance status 0 or 1 6. Able to provide written informed consent 7. Patient has adequate venous access in order to obtain all required blood samples and to undergo Leukapheresis as per protocol Inclusion Criteria Arm 1B: 1. HPV16+ head and neck, cervical, anogenital, penile and unknown primary carcinoma patients with recurrent disease. 2. Intention to treat is palliative 3. Tissue samples available confirming HPV16+ disease to send to Central Laboratory 4. Able to provide written informed consent 5. Patient has adequate venous access in order to obtain all required blood samples and to undergo Leukapheresis as per protocol Previous inclusion criteria: Inclusion Criteria Arm 1A: 1. Previous HPV16+ head and neck squamous cell carcinoma 2. At least 12 months after completion of treatment 3. Within 5 years of treatment completion 4. Currently no clinical evidence of disease 5. ECOG performance status 0 or 1 6. Able to provide written informed consent Inclusion Criteria Arm 1B: 1. HPV16+ head and neck, cervical, anogenital and penile carcinoma patients with recurrent disease. 2. Intention to treat is palliative. 3. Patient willing to have repeated tumour biopsies and re-biopsy deemed safe and feasible clinically. 4. Tissue samples available confirming HPV16+ disease to send to Central Laboratory.
Key exclusion criteria	Current exclusion criteria as of 18/09/2026: 1. Patients unable to consent 2. Any patient who has been previously vaccinated with BNT113 in any Arm of the trial. 3. Under 18 years of age 4. Systemic steroids (>10 mg Prednisolone/day or equivalent) or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry. Replacement steroids for adrenal insufficiency/failure are allowed. 5. Major surgery in the preceding three to four weeks, which the patient has not yet recovered from. 6. Patients who are of high medical risk because of non-malignant systemic disease, as well as those with active uncontrolled infection 7.Patients with clinically relevant autoimmune disease will be excluded. 8.Patients who are known to be allergic to any of the excipients or constituents of the vaccine 9. Patients with any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial, such as concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease 10. Current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. For Arm 1A; cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the trial. For Arm 1B; cancer survivors, who have undergone potentially curative therapy for a prior malignancy and have no evidence of that disease for one year, are eligible for the trial. 11. Patients who are serologically positive for or are known to suffer from Hepatitis B, C, Syphilis or HIV. Counselling will be offered to all patients prior to testing 12. Patients who have a positive pregnancy test or who are breast feeding. 13. Fertile males or females who are unable or unwilling to use a highly effective method of birth control (less than 1% per year, e.g. condom with spermicide, diaphragm with spermicide, birth control pills, injections, patches, intrauterine device, or intrauterine hormone-releasing system) during study treatment and until 28 days after patients finish the trial treatment. 14. Arm 1B patients with the presence of liver metastasis: Elevated Liver Function Tests – ALT >5.0 x ULN, AST >5.0 x ULN, ALP >5.0 x ULN. Patients who are likely to have rapid disease progression may not be good candidates for the trial. In such cases, please discuss with the Chief Investigator. 15. Elevated Liver Function Tests – ALT >3.0 x ULN, AST >3.0 x ULN, Bilirubin >3.0 x ULN. 16. Any other investigational drug within 28 days or 5 half-lives depending on what gives the longer range before the first treatment of this study; exceptions may be possible with discussion with the CI. Previous exclusion criteria: 1. Patients unable to consent 2. Under 18 years of age 3. Systemic steroids or other drugs with a likely effect on immune competence are forbidden during the trial. The predictable need of their use will preclude the patient from trial entry. Replacement steroids for adrenal insufficiency/failure are allowed. 4. Major surgery in the preceding three to four weeks, which the patient has not yet recovered from 5. Patients who are of high medical risk because of non-malignant systemic disease, as well as those with active uncontrolled infection 6. Patients with any other condition which in the Investigator’s opinion would not make the patient a good candidate for the clinical trial, such as concurrent congestive heart failure or prior history of New York Heart Association (NYHA) class III/IV cardiac disease 7. Current malignancies at other sites, with the exception of adequately treated basal or squamous cell carcinoma of the skin. Cancer survivors, who have undergone potentially curative therapy for a prior malignancy, have no evidence of that disease for five years and are deemed at low risk for recurrence, are eligible for the study 8. Patients who are serologically positive for or are known to suffer from Hepatitis B, C, Syphilis or HIV. Counselling will be offered to all patients prior to testing 9. Patients who have a positive pregnancy test 10. Fertile males or females who are unable or unwilling to use a highly effective method of birth control (less than 1% per year, e.g. condom with spermicide, diaphragm with spermicide, birth control pills, injections, patches, intrauterine device, or intrauterine hormone-releasing system) during study treatment and until end of treatment +28 days (day 113) 11. Elevated Liver Function Tests – ALT, AST, Bilirubin 12. Any other investigational drug within 28 days or 5 half-lives depending on what gives the longer range before the first treatment of this study
Date of first enrolment	18/05/2017
Date of final enrolment	19/07/2023

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

University Hospital Southampton

Southampton University Hospital
Tremona Road
Southampton
SO16 6YD
England

The Christie NHS Foundation Trust

550 Wilmslow Road
Withington
Manchester
M20 4BX
England

Results and Publications

Individual participant data (IPD) Intention to share	No

Study outputs

Output type	Date created	Date added	Peer reviewed?	Patient-facing?
Abstract results	01/09/2024	30/09/2026	No	No
Basic results		10/03/2026	No	No
HRA research summary		28/06/2023	No	No
Study website	11/11/2025	11/11/2025	No	Yes

Additional files

ISRCTN51789191_BasicResults.pdf: Basic results

Editorial Notes

30/09/2026: Abstract added.
18/09/2026: The following changes were made to study record:
1. The interventions, primary/secondary outcomes, inclusion/exclusion criteria, and contact details were updated.
2. The date of first enrolment was changed from 01/01/2017 to 18/05/2017.
3. Funder BioNTech SE added.
4. The final enrolment number was changed from 15 to 30.
5. The target sample size was changed from 153 to 44.
10/03/2026: Basic results uploaded.
27/01/2025: The following changes were made:
1. The study type prevention was replaced by treatment.
2. The intention to publish date was changed from 24/01/2025 to 31/10/2025.
3. The publication and dissemination plan was updated.
02/02/2024: The following changes were made to the study record:
1. Ethics approval details added.
2. The overall study end date was changed from 31/07/2024 to 24/01/2024.
3. The intention to publish date was changed from 30/07/2025 to 24/01/2025.
05/09/2023: The recruitment end date was changed from 31/12/2023 to 19/07/2023.
17/04/2023: The following changes have been made:
1. The scientific title has been changed from "Therapeutic HPV vaccine trial +/- anti-CD40 in HPV-driven squamous cell carcinoma" to "Therapeutic HPV vaccine (BNT113) trial in HPV16-driven carcinoma".
2. The intervention name has been added.
3. The final enrolment number has been added.
4. The recruitment end date has been changed from 31/12/2022 to 31/12/2023.
5. University Hospital Southampton and The Christie NHS Foundation Trust have been added to the trial participating centres and Southampton Clinical Trials Unit removed .
17/03/2022: The following changes have been made:
1. The recruitment end date has been changed from 31/03/2022 to 31/12/2022.
2. The overall trial end date has been changed from 31/01/2023 to 31/07/2024.
3. The intention to publish date has been changed from 31/01/2024 to 30/07/2025.
4. The trial website has been added.
5. The study contact has been updated.
07/04/2020: The recruitment end date was changed from 31/01/2021 to 31/03/2022.
04/07/2019: ClinicalTrials.gov number added.
28/03/2019: The condition has been changed from "Specialty: Cancer, Primary sub-specialty: Gynae; UKCRC code/ Disease: Cancer/ Malignant neoplasms of female genital organs, Cancer/ Malignant neoplasms of male genital organs, Cancer/ Malignant neoplasms of ill-defined, secondary and unspecified sites" to "HPV-driven squamous cell carcinoma" following a request from the NIHR.
07/02/2019: The following changes were made:
1. The recruitment end date was changed from 31/01/2019 to 31/01/2021.
2. The overall trial end date was changed from 31/01/2021 to 31/01/2023.
3. Thee intention to publish date was changed from 31/01/2022 to 31/01/2024.
22/01/2018: The recruitment end date was changed from 01/01/2018 to 31/01/2019.
11/08/2017: Cancer Help UK lay summary link added.
06/06/2017: Internal review