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

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.