Weekly Cetuximab/RT Versus Weekly Cisplatin/RT in HPV-Associated Oropharyngeal Squamous Cell Carcinoma

Study Overview
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Brief Summary
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A standard treatment for patients with head and neck cancer is radiation given with high doses of a chemotherapy drug called cisplatin, given every 3 weeks during the radiation. This treatment is effective but can significantly increase side effects such as difficulty with swallowing, a sore mouth, fatigue, hearing loss, ringing in the ears and kidney failure. In Australia, a commonly used treatment HPV-Associated Oropharyngeal Squamous Cell Carcinoma is a lower dose of cisplatin given weekly during the radiation. The high dose and low dose schedules result in a similar total dose of cisplatin being given during the radiation, but it is thought that the weekly schedule results in fewer side effects while maintaining effectiveness. Another approach widely used around the world for patients with head and neck cancer, is to administer the antibody, cetuximab, weekly during radiation. Cetuximab has a very different side effect profile to cisplatin, and has been reported to result in less exacerbation of radiation related side effects. Both cetuximab and cisplatin can reduce the growth of a cancer and increase the effectiveness of radiation. Both cisplatin and cetuximab appear to be effective treatments in combination with radiation, but have not been directly compared. The purpose of this study is to compare the treatment related side effects (both acute and longer term) between the cisplatin and cetuximab regimens. Both treatments would be given with the same dose of radiation therapy over 7 weeks. The results of this trial will help determine the optimal treatment for patients with HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

Detailed Description
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Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence and has an improved prognosis compared to other head and neck malignancies when treated with standard combination chemoradiation. The current standard regimen of high dose cisplatin and Radiation Therapy (RT) for head and neck cancer patients results in significant toxicity and is at the limits of tolerance. The excellent prognosis of patients with HPV-positive OPSCC raises concerns about overtreatment with the current standard of care, resulting in unnecessary acute and late morbidity. Therefore, investigation of chemo-sparing or chemo-modified regimens with RT for HPV-associated OPSCC that do not compromise efficacy is warranted. A number of regimens less intensive than high dose cisplatin are being used in clinical practice for patients with good prognosis HPV OPSCC, but no comparative trials have been performed in this population. The trial population will be restricted to low risk HPV-associated OPSCC. Trial Arms: A- RT (70 Gy in 35 fractions, 5 days a week over 7 weeks) with weekly Cetuximab (400 mg/m2 loading dose IV prior to radiation, followed by weekly cetuximab 250 mg/m2 for the duration of the radiotherapy) B- RT(70 Gy in 35 fractions, 5 days a week over 7 weeks) with weekly Cisplatin (40 mg/m2 IV for the duration of the radiotherapy) Hypothesis: In patients with locally advanced HPV-associated OPSCC, those treated with weekly cetuximab and conventionally fractionated radiotherapy will experience less acute symptom severity than patients receiving weekly cisplatin and conventionally fractionated radiotherapy. Patients will be followed weekly during treatment, then at 1, 3, 5, 9, 13 weeks post-treatment and at months 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 42, 48, 54, and 60 post-completion of treatment. Follow-up for the trial will cease when the last patient accrued has a minimum of 2 years follow-up i.e. has attended the 24 months post-treatment review.

Official Title
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TROG12.01 A Randomised Trial of Weekly Cetuximab and Radiation Versus Weekly Cisplatin and Radiation in Good Prognosis Locoregionally Advanced HPV-Associated Oropharyngeal Squamous Cell Carcinoma

Conditions
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HPV Positive Oropharyngeal Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: Cetuximab
* Radiation: RT (70 Gy in 35 fractions)
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years or older Has provided written Informed Consent for participation in this trial Histologically confirmed squamous cell carcinoma of the oropharynx with p16 positive status confirmed locally by immunohistochemistry Stage III (excluding T1-2N1) or stage IV (excluding T4, N3, and distant metastasis) if smoking history of < /=10 pack years. If > 10 pack years nodal disease must be N0 - N2a. If an excisional biopsy has been performed, patients remain eligible for the study provided there is clinically measurable disease prior to commencing RT. The residual disease should still meet the stage criteria required for the trial e.g. excisional biopsy of a node with residual T3 primary, or tonsillectomy for T1 primary with residual > N2a nodes. No prior treatment for oropharyngeal cancer Adequate haematological, renal, and hepatic function as defined by, Absolute neutrophil count (ANC, segs + bands) > /= 1.5 x 109/L Platelet count > /= 100 x 109/L Total bilirubin < /= 1.5 x upper normal limit ALT < /= 2.5 x upper normal limit Calculated creatinine clearance (Cockcroft-Gault formula) or isotopic GFR > 55ml/min ECOG performance status score of 0-1 Participants capable of childbearing are using adequate contraception and intend to continue use of contraception for at least 6 months following completion of treatment Negative pregnancy test within 72 hours prior to randomisation of women who are of childbearing potential Suitable for follow-up for at least 24 months as per trial protocol. Sufficient proficiency in English, cognitive capacity and willingness to complete questionnaires Exclusion Criteria: History of unknown primary of the head and neck T4, N3 or distant metastases Smoking history >10 pack years with N2b or c nodal status Women who are pregnant or lactating. Previous radiotherapy to the area to be treated (excluding superficial radiotherapy for a cutaneous malignancy) Previous cisplatin or carboplatin chemotherapy Prior EGFR targeted therapy of any kind Primary surgery to the affected area (excisional biopsy allowed) Peripheral neuropathy > /= grade 2 (CTCAE v4.0) Sensori-neural hearing impairment >= grade 2 (CTCAE v4.0, hearing impaired, not enrolled on a monitoring program) which may be exacerbated by cisplatin (Audiometric abnormalities without corresponding clinical deafness will not be grounds for exclusion) Tinnitus > /= grade 2 (CTCAE v4.0) History of interstitial lung disease or evidence of interstitial lung disease on pre-registration CT History of myocardial infarction within 12 months prior to study entry, uncontrolled congestive heart failure, unstable angina, active cardiomyopathy, unstable arrhythmia, uncontrolled psychotic disorders, active serious infections, active peptic ulcer disease, immunosuppression due to post-organ transplantation or use of immunosuppressants for autoimmune disorders Patients known to be HIV positive Other cancer that was diagnosed: more than 5 years prior to current diagnosis with (i) subsequent evidence of disease recurrence or (ii) clinical expectation of recurrence is greater than 10% or within 5 years of the current diagnosis, with the exception of successfully treated basal cell or squamous cell skin carcinoma, in situ melanoma, or carcinoma in situ of the cervix

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Radiation Therapy + Cetuximab<br>RT (70 Gy in 35 fractions, 5 days a week over 7 weeks) with weekly Cetuximab (400 mg/m2 loading dose IV prior to radiation, followed by weekly cetuximab 250 mg/m2 for the duration of the radiotherapy) | Drug: Cetuximab<br> <br> Radiation: RT (70 Gy in 35 fractions)<br> <br> |
| Active Comparator: Radiation Therapy + Cisplatin<br>RT(70 Gy in 35 fractions, 5 days a week over 7 weeks) with weekly Cisplatin (40 mg/m2 IV for the duration of the radiotherapy) | Radiation: RT (70 Gy in 35 fractions)<br> <br> Drug: Cisplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom Severity | The area under curve of symptom severity between weekly cisplatin and Radiotherapy Therapy (RT) versus weekly cetuximab and RT from baseline to week 20 (13 weeks post-completion of radiotherapy) as measured by M.D. Anderson Symptom Inventory - Head and Neck Module (MDASI-HN). | 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptom severity | Symptom severity measured by MDASI-HN (Symptom Interference Score, Symptom Score, Symptom Clusters and individual item scores at individual time points)and by Functional Assessment of Cancer Therapy - Head and Neck (FACT-HN). | 24 months | 
| Interference of symptoms with daily life | To compare interference of symptoms with daily life using the MDASI-HN Symptom Interference Score and Quality adjusted life years (QALYs) using the EQ-5D-5L | 24 mths | 
| Psychological distress | To compare psychological distress measured by FACT-HN domain scores and depression and anxiety scales of Hospital Anxiety and Depression Scale (HADS) | 36 months | 
| Impact on Health Related Quality of Life |  | 36 months | 
| Swallowing dysfunction | To compare swallowing dysfunction by Functional swallowing outcome (video fluoroscopy), CTCAE (v4.0) dysphagia, MDASI and FACT questionnaires, enteral feeding rates. | 12 months | 
| Speech and dietary function | To compare speech and dietary function as measured by the Performance Status Scale for Head & Neck Cancer Patients (PSS-HN) | 36 months | 
| Clinician-assessed acute and late toxicity | To compare clinician-assessed acute and late toxicity using toxicity grading (CTCAE v4.0) - reported as worst toxicity and as overall acute toxicity burden (T-score) | 60 months | 
| Rate of enteral feeding | To compare rate of enteral feeding at 12 months following treatment using Barnard's exact test for the comparison of two proportions | 12 months | 
| Hearing impairment | To compare hearing impairment, as measured by total score of the Hearing Handicap Inventory for adults, screening version (HHIA-S) and audiometry (results will be evaluated according to CTCAE 3 and 4 criteria, Brock criteria, Chang criteria and SIOP Boston Ototoxicity Scale). | 24 months | 
| Time to locoregional failure | To compare time to locoregional failure primarily determined by evidence of progression or recurrence clinically or radiologically | 36 months | 
| Failure-free survival | To compare failure-free survival by clinical and radioloigical assessments | 36 months | 
| Overall survival | To compare overall survival by clinical assessment. | 60 months | 
| Pattern of disease failure | Pattern of disease failure (locoregional [recurrence at primary tumour site and/or regional nodes], distant, both) as assessed radiologically. | 36 months | 
| Complete response rate | To compare FDG-PET-CT complete response rate at week 20 | 20 weeks | 
| Cost of health resource utilisation | To compare cost of health resource utilisation via questionnaires EQ-5D-5L and RTOG return to work questionnaire. | 24 months | 
| Work status and time to return to work | To compare work status and time to return to work by RTOG questionnaire | 24 months | 
| Potential prognostic markers | To correlate several potential prognostic markers (including but not limited to EGFR protein level, EGFR copy number, ERCC1, plasma hepatocyte growth factor level, and plasma IL-8) with failure-free survival, overall survival and time to locoregional failure. | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human Papilloma Virus, HPV, Oropharyngeal, Squamous Cell, Carcinoma