Last updated on March 2019

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

Brief description of study

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 feasibility of recruitment- if the phase II recruits successfully, PATHOS will continue to a Phase III study aiming to show non-inferiority of survival in the reduced intensity treatment arms.

Detailed Study Description

PATHOS is a multicentre, open label, parallel group Phase II/III randomised controlled trial (RCT). Approximately 242 patients will be recruited to the phase II 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 determined, HPVpositive 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.

Surgery to the primary site may be carried out by Transoral Laser Microsurgery (TLM) or Transoral Robotic Surgery (TORS), whilst a standard open approach will be used to facilitate an associated neck dissection.

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

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

Group B: Patients with: T3 tumours (or T1T2 tumours with additional risk factors), N2a (metastasis in single ipsilateral node 31-60 mm diameter) or N2b (metastasis in multiple ipsilateral nodes <61 mm diameter) disease with evidence of perineural and/or vascular invasion or close margins (15mm) around the primary tumour specimen but with negative marginal biopsies (section 7.1). 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: Patients with tumours of any T or any N stage, which exhibit the following high risk pathological features will be included: positive (<1mm) margins around the primary tumour specimen but with negative marginal biopsies and/or evidence of cervical lymph node extracapsular spread. Patients 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 only (Test Arm C2).

Patients in groups B and C will be stratified prior to 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.

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

The time point of assessments should be recorded on the CRF. Complications relating to surgery will be recorded in the CRF. In particular any complications which necessitate a delay to the start of adjuvant treatment.

The Phase II study will, if successful in demonstrating a swallowing function advantage in the experimental arms, continue seamlessly onto a phase III study, the primary endpoint of which is overall survival, aiming to prove survival noninferiority in the reduced intensity treatment arms. In order to demonstrate survival noninferiority, >800 patients in total will need to be recruited. The phase II will act as an internal pilot and recruited patients will be included in the phase III study.

Data registry: The top copy of each completed CRF should be returned to the WCTU for data entry within four weeks of the visit. The remaining copy is to be retained at the local site. In accordance with the principles of GCP, the PI is responsible for ensuring accuracy, completeness, legibility and timeliness of the data reported to the WCTU in the CRFs.CRF pages and data received by the WCTU from participating trial sites 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. The data clarification form will be sent to the relevant participating site. The site shall be requested to answer the data query or correct data on the data clarification form. The CRF pages should not be altered.

All answered data queries and corrections should be signed off and dated by a delegated member of staff at the relevant participating site. The completed data clarification form should be returned to the WCTU and a copy retained at the site along with the participants' CRFs.

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

Quality assirance: 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: To register or randomise a patient the relevant registration or randomisation case report form (CRF) should be completed and the Wales Clinical Trials Unit (WCTU) contacted. Randomisation will take place centrally after confirmation of eligibility, by a telephone call to the WCTU. Participants will be randomised using minimisation with a random element. This will ensure balanced treatment allocation by a number of clinically important stratification factors. Randomisation will have an allocation ratio of 1:1.

Statistical analyses: We will compare mean MDADI scores at 12 months between arms using either a t-test or nonparametric methods if appropriate depending upon distributions. We expect baseline MDADI values to be high but will adjust for these and the randomisation stratification variables in additional sensitivity analyses using regression techniques. This primary analysis will be conducted when the last patient has had their 12 month assessment. A detailed statistical analysis plan will be developed before the analyses are conducted.

An IDMC will review the accumulating data (survival, toxicities, recruitment) at 6 monthly intervals (see section 13.1). Additionally, using a similar method to the CTAAC funded PARSPORT trial (CRUK/03/005), a formal interim analysis will be performed after 38 patients have been randomised in each randomisation (19 per arm), treated and followed up for 6 months. Within each randomisation, a stopping rule will be based on observing an absolute observed difference of 6 or more loco-regional recurrences and/or deaths as reason to consider early termination of the trial.

However, the IDMC will also be asked to take into account available data from other sources and the likely influence on clinical practice before recommending early closure of the trial. Once the 12 month follow- up data has been accumulated to answer the Phase II question, the IDMC will be convened to recommend either continuing to Phase III or stopping recruitment. In making this decision they will consider both the primary and secondary endpoint data.

Sub-group statistical analyses:

For swallowing endpoints, subgroup analysis by T stage and tumour subsite (tonsil, soft palate, tongue base) will be carried out, as the most likely relevant clinical co-variables affecting swallowing function. Exploratory analyses may be conducted to aid hypothesis generation if a phase III is subsequently developed.

Clinical Study Identifier: NCT02215265

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Newcastle upon Tyne Hospitals NHS Foundation Trust

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Institute of Health and Society

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