Clinical trial NCT02215265: Post-operative Adjuvant Treatment for HPV-positive Tumours (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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Human Papillomavirus (HPV)-Positive Oropharyngeal Cancer
Keywords: Human papillomavirus HPV positive oropharyngeal cancer
Lead sponsor: Velindre NHS Trust
Sponsor class: OTHER_GOV
Collaborators: name: UNICANCER
name: AdventHealth
name: University of Leipzig
name: Princess Alexandra Hospital, Brisbane, Australia
name: Stanford University
First posted: 2014-08-13
Enrollment: 1269
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

In March 2024, a protocol amendment increasing the target recruitment to Phase III of the study from 1100 to 1269 patients was approved. 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.

Eligibility criteria: 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.

Primary outcomes:
measure: MDADI/Overall survival co-primary endpoint
timeFrame: At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.
Secondary outcomes:
measure: Swallowing panel including qualitative and quantitative swallowing assessments
timeFrame: 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.
measure: QOL (using validated EORTC QLQ C30 and HN35 questionnaires)
timeFrame: 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.
measure: Acute and late toxicity using CTACE version 4.03
timeFrame: 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.
measure: Disease Free Survival
timeFrame: 6 months intervals
measure: Locoregional control
timeFrame: 6 months intervals
measure: Distant Metastases
timeFrame: 6 months intervals
Other outcomes:
Locations:
city: Redwood City
country: United States
facility: Board of Trustees of the Leland Stanford Junior University
state: California
city: Orlando
country: United States
facility: Advent Health
state: Florida
city: Houston
country: United States
facility: MD Anderson Cancer Centre
state: Texas
city: Brisbane
country: Australia
facility: Metro South Health
city: Paris
country: France
facility: Unicancer
city: Berlin
country: Germany
facility: Vivantes Klinikum
city: Giessen
country: Germany
facility: Zentrum für Hals-, Nasen- und Ohrenheilkunde
city: Hamburg
country: Germany
facility: Asklepios Kliniken
city: Hamburg
country: Germany
facility: Kath Marienkrankenhaus gGmbH
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Leipzig
country: Germany
facility: Universitat Leipzig
city: Potsdam
country: Germany
facility: Ernst von Bergmann Klinikum
city: Solingen
country: Germany
facility: Städtisches Klinikum Solingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Poole
country: United Kingdom
facility: University Hospitals Dorset NHS Foundation
state: Dorset
city: Bath
country: United Kingdom
facility: Royal United Hospitals Bath NHS Foundation Trust
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
city: Cardiff
country: United Kingdom
facility: HPV Research Group Section of Pathology Cardiff University ,School of Medicine
city: Cardiff
country: United Kingdom
facility: Cardiff and Vale University Local Health Board
city: Cardiff
country: United Kingdom
facility: Centre for Trials Research
city: Cardiff
country: United Kingdom
facility: Velindre NHS Trust
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
city: Derby
country: United Kingdom
facility: Derby Teaching Hospitals NHS Foundation Trust
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon University Health Care NHS Foundation Trust
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: Liverpool
country: United Kingdom
facility: Liverpool Head and Neck Centre
city: Liverpool
country: United Kingdom
facility: University of Liverpool
city: Llantrisant
country: United Kingdom
facility: Cwm Taf Bro Morganwg
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Guys and St Thomas's NHS Foundation Trust
city: London
country: United Kingdom
facility: St Georges University Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Pennine Acute Hospital Trust
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital
city: Newcastle upon Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospitals NHS Foundation Trust
city: Newport
country: United Kingdom
facility: Aneurin Bevan University Health Board
city: Northampton
country: United Kingdom
facility: Northampton General Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation Trust
city: Plymouth
country: United Kingdom
facility: University Hospital Plymouth
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
city: Stoke
country: United Kingdom
facility: Royal Stoke Hospital
city: Sunderland
country: United Kingdom
facility: City Hospitals Sunderland NHS Foundation Trust
city: Swansea
country: United Kingdom
facility: Swansea Bay University Local Health Board
Study officials:
affiliation: Velindre NHS Trust
name: Mererid Evans, MBBch, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aintree University Hospital
name: Terrence Jones, MBBS,MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Owadally W, Hurt C, Timmins H, Parsons E, Townsend S, Patterson J, Hutcheson K, Powell N, Beasley M, Palaniappan N, Robinson M, Jones TM, Evans M. PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer. BMC Cancer. 2015 Aug 27;15:602. doi: 10.1186/s12885-015-1598-x.