Post-operative Adjuvant Treatment for HPV-positive Tumours (PATHOS)

Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer Clinical Trial

— PATHOS  

Official title:

A Phase III Trial of Risk-stratified, Reduced Intensity Adjuvant Treatment in Patients Undergoing Transoral Surgery for Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02215265
• Other study ID #: 2014/VCC/0014
• Status: Recruiting
• Phase: Phase 3
• Start date: October 2015
• Est. completion date: April 2027

Study information

• Verified date: July 2023
• Source: Velindre NHS Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The main objectives of the PATHOS study are:

To assess whether swallowing function can be improved following transoral resection of HPV-positive OPSCC, by reducing the intensity of adjuvant treatment protocols. The aim is to personalise treatment, based on disease biology (HPV status and pathology findings), to optimise patient outcomes.

To demonstrate the non-inferiority of reducing the intensity of adjuvant treatment protocols in terms of overall survival in the reduced intensity treatment arms.

Description:

PATHOS is a multicentre, open-label, parallel-group Phase II/III randomised controlled trial (RCT). The phase II target of 242 patients was reached in December 2018 and there was a seamless transition into Phase III. The protocol was amended in September 2018 to incorporate the changes associated with the phase III transition. The amendment included changes to the outcome measures and sample size calculations.

Approximately 1100 patients will be recruited to the phase III study. Patients eligible for the study must have biopsy proven oropharyngeal squamous cell carcinoma (OPSCC) clinically staged T1T3 N0N2b. Their primary tumour, as judged by the local MDT, must be considered resectable via a transoral approach. Having secured informed consent, patients with centrally or locally determined HPV positive tumours will undergo baseline assessment of swallowing function (includes; MDADI score, videofluoroscopy, PSSH& N, 100 mL water swallow test) and complete QOL questions (EORTC QLQC30 and EORTC QLQH&N35) prior to surgery.

Transoral Laser Microsurgery, Transoral Robotic Surgery & Endoscopically assisted Transoral Surgery are all accepted transoral techniques for the study. A lateral oropharyngectomy performed with monopolar cautery (The Huet Procedure) can also be used.

Following surgery and histopathological assessment of the primary tumour and neck dissection surgical specimens, participants will be allocated into study groups based on the presence or absence of pathological risk factors for recurrence as follows:

Group A: Participants with tumours which exhibit no adverse histological features. Participants in this group will not receive any adjuvant treatment as per standard of care.

Group B: Participants with T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes <61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour. Patients in this group will be randomised to PORT 60Gy in 30# over 6 weeks (Control Arm B1) or PORT 50Gy in 25# over 5 weeks (Test Arm B2).

Group C: Participants with tumours of any T or any N stage, which exhibit the following high-risk pathological features will be included: A histologically normal tissue margin around the primary tumour of <1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease. Participants in this group will be randomised to POCRT 60Gy in 30# over 6 weeks with concurrent Cisplatin (Control Arm C1) or PORT 60Gy in 30# over 6 weeks without chemotherapy (Test Arm C2).

Participants in groups B and C will be stratified before randomisation by T stage, N stage, smoking history and treating centre.

The same assessments as at baseline will be completed post-operatively prior to treatment and then at four weeks and 6, 12 and 24 months post-treatment. The exception is videofluoroscopy which will be repeated at post-surgery and 12 months only. Videofluroscopies are only performed at UK sites.

Acute and late toxicity will be recorded weekly during treatment and again at 4 weeks and 6, 12 and 24 months post-treatment.

All study assessments, complications relating to surgery and adjuvant treatment, in particular complications which necessitate a delay to the start of adjuvant treatment, will all be recorded on the Case Report Form (CRF).

International sites have been initiated on Electronic Data Capture (EDC) and local UK sites have transitioned to EDC for participants enrolled after implementation. Data entry needs to be completed within four weeks of the study visit. In accordance with the principles of GCP, the PI is responsible for ensuring accuracy, completeness, legibility and timeliness of the data reported to the CTR in the CRFs. The CRF will be checked for missing, illegible or unusual values (range checks) and consistency over time.

If missing or questionable data are identified, a data query will be raised on a data clarification form and sent to the site for resolution. All answered data queries and corrections should be signed off and dated by a delegated member of staff at the relevant participating site.

The CTR will send reminders for any overdue data. It is the site's responsibility to submit complete and accurate data in a timely manner.

Quality assurance: The clinical trial risk assessment has been used to determine the intensity and focus of central and on-site monitoring activity in the PATHOS trial. Monitoring levels will be employed and are fully documented in the trial monitoring plan. Investigators should agree to allow trial-related monitoring, including audits and regulatory inspections, by providing direct access to source data/documents as required. Patient consent for this will be obtained.

Registration: All sites have transitioned to an electronic database and the registration and randomisation process is completed online. Participants will be randomised using minimisation with a random element. This will ensure balanced treatment allocation by clinically important stratification factors. Randomisation will have an allocation ratio of 1:1.

Statistical analyses:

Primary outcome measure

MDADI/Overall survival co-primary endpoint

Secondary outcome measures

• Swallowing panel including qualitative and quantitative swallowing assessments (100ml Water Swallow Test, Videofluoroscopy, Performance Status Scale-Head & Neck)

• QOL (using validated EORTC QLQ C30 and HN35 questionnaires, Appendix 6)

• Acute and late toxicity using CTACE version 4.03

• Disease-Free Survival*

• Locoregional control*

• Distant Metastases* *Determined by clinical follow-up as per standard guidelines (no trial-specific imaging required)

The co-primary endpoint of the Phase III will be MDADI and overall survival (time to event).

We will use linear regression to estimate the treatment arm effect on MDADI at 12 months and will include the randomisation stratification variables and baseline MDADI in the model. Both OS and MDADI endpoints will be used to define study success so no adjustment for multiplicity is planned. A detailed statistical analysis plan will be developed before the analyses are conducted.

The data will be reviewed (approximately six-monthly) by an Independent Data Monitoring Committee (IDMC), consisting of at least two Clinicians (not entering patients into the trial) and an independent Statistician. The IDMC will be asked to recommend whether the accumulated data from the trial, together with results from other relevant trials, justifies continuing recruitment of further patients. A decision to discontinue recruitment, in all patients or selected subgroups, will be made only if the result is likely to convince a broad range of Clinicians including PIs in the trial and the general clinical community. If a decision is made to continue, the IDMC will advise on the frequency of future reviews of the data based on accrual and event rates.

Sub-group statistical analyses:

For swallowing endpoints, subgroup analysis by T stage and tumour subsite (tonsil, soft palate, tongue base) and surgery technique will be carried out, as the most likely relevant clinical co-variables affecting swallowing function.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1100
• Est. completion date: April 2027
• Est. primary completion date: October 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed or suspected squamous cell carcinoma of the oropharynx.

• UICC/AJCC TNM 7th edition stage T1-T3, N0-N2b (or UICC TNM 8th edition stage T1-T3, N0-N1) disease.

• Multidisciplinary team (MDT) decision to treat with primary transoral resection and neck dissection.

• Patients considered fit for surgery and adjuvant radiotherapy

• Aged 18 or over.

• Written informed consent provided.

Exclusion Criteria:

• Known HPV negative squamous cell carcinomas of the head and neck: A negative result for p16 Immunohistochemistry automatically excludes a patient from the trial. If initial p16 testing is positive but High Risk HPV (HR HPV) In-Situ Hybridization (ISH)/Polymerase Chain Reaction (PCR) does not demonstrate the presence of HR HPV DNA, the patient will also be excluded. Patients who are p16+ may complete swallowing assessments, excluding videofluoroscopy, and surgery whilst HR HPV DNA status is being determined (with recourse to central concordance testing, if appropriate, for UK centres). HPV positivity, as determined by p16 and the demonstration of HR HPV DNA is essential before patients undergo videofluoroscopy or randomisation.

• T4 and/or T1-T3 tumours where transoral surgery is considered not feasible.

• UICC/AJCC TNM 7th edition N2c-N3 nodal disease (or UICC/AJCC TNM 8th edition N2-N3 nodal disease).

• Patients for whom transoral surgery and neck dissection is not considered the primary treatment modality.

• Current smokers with clinically staged N2b disease (including smokers up to 6 months before diagnosis), even if HPV-positive. Vaping is permitted and should be considered as non-smoking status.

• Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre-existing swallowing dysfunction prior to index oropharyngeal cancer.

• Patients with distant metastatic disease as determined by routine pre-operative staging radiological investigations e.g., CT thorax and upper abdomen or PET-CT.

• Patients with a history of malignancy in the last 5 years, except basal cell carcinoma of the skin or carcinoma in-situ of the cervix.

• Women who are pregnant or breastfeeding and fertile women who will not be using contraception during the trial.

Related Conditions & MeSH terms

• Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer
• Oropharyngeal Neoplasms

Intervention

Drug:
• Cisplatin
Chemotherapy

Radiation:
• Postoperative radiotherapy
Postoperative radiotherapy (PORT)

Locations

Country	Name	City	State
Australia	Metro South Health	Brisbane
France	Unicancer	Paris
Germany	Vivantes Klinikum	Berlin
Germany	Asklepios Kliniken	Hamburg
Germany	Universitat Leipzig	Leipzig
Germany	Ernst von Bergmann Klinikum	Potsdam
Germany	Städtisches Klinikum Solingen	Solingen
Germany	Universitätsklinikum Ulm	Ulm
United Kingdom	Royal United Hospitals Bath NHS Foundation Trust	Bath
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Royal Blackburn Hospital	Blackburn
United Kingdom	Royal Sussex County Hospital	Brighton
United Kingdom	University Hospitals Bristol NHS Foundation Trust	Bristol
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Kent and Canterbury Hospital	Canterbury
United Kingdom	Cardiff and Vale University Local Health Board	Cardiff
United Kingdom	Centre for Trials Research	Cardiff
United Kingdom	HPV Research Group Section of Pathology Cardiff University ,School of Medicine	Cardiff
United Kingdom	Velindre NHS Trust	Cardiff
United Kingdom	Castle Hill Hospital	Cottingham
United Kingdom	Derby Teaching Hospitals NHS Foundation Trust	Derby
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Royal Devon University Health Care NHS Foundation Trust	Exeter
United Kingdom	Royal Surrey County Hospital	Guildford
United Kingdom	St James University Hospital	Leeds
United Kingdom	Liverpool Head and Neck Centre	Liverpool
United Kingdom	University of Liverpool	Liverpool
United Kingdom	Cwm Taf Bro Morganwg	Llantrisant
United Kingdom	Guys and St Thomas's NHS Foundation Trust	London
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	St Georges University Hospital	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	Central Manchester University Hospital NHS Foundation Trust	Manchester
United Kingdom	The Christie NHS Foundation Trust	Manchester
United Kingdom	The Pennine Acute Hospital Trust	Manchester
United Kingdom	The James Cook University Hospital	Middlesbrough
United Kingdom	Newcastle upon Tyne Hospitals NHS Foundation Trust	Newcastle upon Tyne
United Kingdom	Royal Victoria Infirmary	Newcastle upon Tyne
United Kingdom	Aneurin Bevan University Health Board	Newport
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Oxford University Hospitals NHS Foundation Trust	Oxford
United Kingdom	University Hospital Plymouth	Plymouth
United Kingdom	University Hospitals Dorset NHS Foundation	Poole	Dorset
United Kingdom	Queen Alexandra Hospital	Portsmouth
United Kingdom	Royal Preston Hospital	Preston
United Kingdom	Royal Berkshire Hospital	Reading
United Kingdom	University Hospital Southampton	Southampton
United Kingdom	City Hospitals Sunderland NHS Foundation Trust	Sunderland
United Kingdom	Swansea Bay University Local Health Board	Swansea
United States	MD Anderson Cancer Centre	Houston	Texas
United States	Advent Health	Orlando	Florida
United States	Board of Trustees of the Leland Stanford Junior University	Redwood City	California

Sponsors (6)

Lead Sponsor	Collaborator
Lisette Nixon	AdventHealth, Princess Alexandra Hospital, Brisbane, Australia, Stanford University, UNICANCER, University of Leipzig

Countries where clinical trial is conducted

United States,  Australia,  France,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MDADI/Overall survival co-primary endpoint		At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.
Secondary	Swallowing panel including qualitative and quantitative swallowing assessments	Water swallow test	Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment.
Secondary	QOL (using validated EORTC QLQ C30 and HN35 questionnaires)	Quality of Life (QOL) questions.	Baseline; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks) post treatment; 6 months (+/- 4 weeks) post treatment; 12 months (+/- 4 weeks) post treatment; 24 months (+/- 8 weeks) post treatment.
Secondary	Acute and late toxicity using CTACE version 4.03	Toxicity assessment	Weekly during RT and at end of treatment; 4 weeks (+/- 2 weeks) post-surgery, prior to start of any adjuvant treatment; 4 weeks (+/- 2 weeks), 6 months (+/- 4 weeks), 12 months (+/- 4 weeks), and 24 months (+/- 8 weeks) post treatment.
Secondary	Disease Free Survival	Determined by clinical follow up as per standard guidelines	6 months intervals
Secondary	Locoregional control	Determined by clinical follow up as per standard guidelines	6 months intervals
Secondary	Distant Metastases	Determined by clinical follow up as per standard guidelines	6 months intervals