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

ISRCTN	ISRCTN51789191
DOI	https://doi.org/10.1186/ISRCTN51789191
EudraCT/CTIS number	2014-002061-30
ClinicalTrials.gov number	NCT03418480
Secondary identifying numbers	30900

Submission date: 02/11/2016
Registration date: 15/12/2016
Last edited: 27/01/2025

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

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English Summary

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

Study website

Contact information

Miss Izabela Eberhart
Public

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

Phone	+44 23 8120 3522
Email	HARE-40@soton.ac.uk

Study information

Study design	Non-randomized interventional study
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	Therapeutic HPV vaccine (BNT113) trial in HPV16 driven carcinoma
Study acronym	HARE-40
Study hypothesis	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
Condition	HPV-driven squamous cell carcinoma
Intervention	-
Intervention type	Biological/Vaccine
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	BNT113
Primary outcome measure	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.
Secondary outcome measures	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
Overall study start date	01/03/2014
Overall study end date	24/01/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	Planned Sample Size: 153; UK Sample Size: 153
Total final enrolment	15
Participant 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.
Participant 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
Recruitment start date	01/01/2017
Recruitment end date	19/07/2023

Locations

Countries of recruitment

England
United Kingdom

Study participating centres

University Hospital Southampton

Southampton University Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

The Christie NHS Foundation Trust

550 Wilmslow Road
Withington
Manchester
M20 4BX
United Kingdom

Sponsor information

University Hospital Southampton NHS Foundation Trust
Hospital/treatment centre

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
England
United Kingdom

"ROR"	https://ror.org/0485axj58

Funders

Funder type

Government

European Commission
Government organisation / National government

Alternative name(s): European Union, Comisión Europea, Europäische Kommission, EU-Kommissionen, Euroopa Komisjoni, Ευρωπαϊκής Επιτροπής, Европейската комисия, Evropské komise, Commission européenne, Choimisiúin Eorpaigh, Europskoj komisiji, Commissione europea, La Commissione europea, Eiropas Komisiju, Europos Komisijos, Európai Bizottságról, Europese Commissie, Komisja Europejska, Comissão Europeia, Comisia Europeană, Európskej komisii, Evropski komisiji, Euroopan komission, Europeiska kommissionen, EC, EU

Results and Publications

Intention to publish date	31/10/2025
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	Current publication and dissemination plan as of 27/01/2025: Planned publication in a peer-reviewed journal. The Southampton Clinical Trials Unit will publish the results of the trial on its website when these are available. Previous publication and dissemination plan: Planned publication in a high-impact peer reviewed journal.
IPD sharing plan	The current data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

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