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JOURNAL ONKOLOGIE – STUDIE
PATHOS

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

Rekrutierend

NCT-Nummer:
NCT02215265

Studienbeginn:
Oktober 2015

Letztes Update:
21.07.2023

Wirkstoff:
Cisplatin

Indikation (Clinical Trials):
Oropharyngeal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Lisette Nixon

Collaborator:
UNICANCER, AdventHealth, University of Leipzig, Princess Alexandra Hospital, Brisbane, Australia, Stanford University,

Studienleiter

Mererid Evans, MBBch, PhD
Principal Investigator
Velindre NHS Trust
Terrence Jones, MBBS,MD
Principal Investigator
Aintree University Hospital

Studienlocations
(3 von 52)

Städtisches Klinikum Solingen
42653 Solingen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
A.M Sesterhenn
Phone: 00492125472738
E-Mail: sesterhenn@klinikumsolingen.de» Ansprechpartner anzeigen
Leberkrebszentrum Universitätsklinikum Ulm
Albert-Einstein-Allee 23
89081 Ulm
DeutschlandRekrutierend» Google-Maps
Ansprechpartner:
Simon Laban
Phone: 0731 500 59543
E-Mail: Simon.laban@uniklinik-ulm.de» Ansprechpartner anzeigen
Board of Trustees of the Leland Stanford Junior University
94063 Redwood City
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Michelle Chen
Phone: 650-723-5957
E-Mail: nbedi@stanford.edu» Ansprechpartner anzeigen
Advent Health
32803 Orlando
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Bruce Haughey
Phone: 407-303-0409
E-Mail: bruce.haughey.md@flhosp.org

Sara Guyler
Phone: 407-543-4000
Phone (ext.): 1203655
E-Mail: Sara.Guyler@AdventHealth.com» Ansprechpartner anzeigen
MD Anderson Cancer Centre
77030 Houston
United StatesAktiv, nicht rekrutierend» Google-Maps
HPV Research Group Section of Pathology Cardiff University ,School of Medicine
CF14 4XN Cardiff
United KingdomNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Ned Powell, Dr
E-Mail: PowellNG@cardiff.ac.uk» Ansprechpartner anzeigen
Central Manchester University Hospital NHS Foundation Trust
M13 9WL Manchester
United KingdomRekrutierend» Google-Maps
Ansprechpartner:
Jarrod Homer, Professor
E-Mail: jarrod.j.homer@manchester.ac.uk» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

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.

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.

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. MDADI/Overall survival co-primary endpoint (Time Frame - At 12 months following treatment measured using the MD Anderson Dysphagia Inventory (MDADI) score.)



Secondary outcome:

1. Swallowing panel including qualitative and quantitative swallowing assessments (Time Frame - 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.):
Water swallow test

2. QOL (using validated EORTC QLQ C30 and HN35 questionnaires) (Time Frame - 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.):
Quality of Life (QOL) questions.

3. Acute and late toxicity using CTACE version 4.03 (Time Frame - 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.):
Toxicity assessment

4. Disease Free Survival (Time Frame - 6 months intervals):
Determined by clinical follow up as per standard guidelines

5. Locoregional control (Time Frame - 6 months intervals):
Determined by clinical follow up as per standard guidelines

6. Distant Metastases (Time Frame - 6 months intervals):
Determined by clinical follow up as per standard guidelines

Studien-Arme

  • No Intervention: A: No adjuvant treatment
    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.
  • Active Comparator: B1: Postoperative radiotherapy 60 Gray
    Arm B1: postoperative radiotherapy (PORT) at a dose of 60 Gray (Gy) in 30 fractions over 6 weeks. Group B: Patients 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.
  • Experimental: B2: Postoperative radiotherapy 50 Gray
    Arm B2: Postoperative radiotherapy (PORT) at a dose 50 Gray in 25 fractions over 5 weeks. Group B: Patients 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.
  • Active Comparator: C1: Postoperative radiotherapy 60 Gray with Cisplatin
    Arm C1: postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks with concurrent Cisplatin chemotherapy (POCRT). Cisplatin may be given 3 weekly (100mg/m2 week 1 and week 4 of radiotherapy) or weekly (40mg/m2 weekly during radiotherapy), according to local practice. Group C: Patients 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
  • Experimental: C2: Postoperative radiotherapy 60 Gray without chemotherapy
    Arm C2: Postoperative radiotherapy at a dose of 60 Gray in 30 fractions over 6 weeks without chemotherapy (Test Arm C2). Group C: Patients 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

Geprüfte Regime

  • Cisplatin:
    Chemotherapy
  • Postoperative radiotherapy:
    Postoperative radiotherapy (PORT)

Quelle: ClinicalTrials.gov


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