Clinical Trials /

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

NCT01855451

Description:

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.

Related Conditions:
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Weekly Cetuximab/RT Versus Weekly Cisplatin/RT in HPV-Associated Oropharyngeal Squamous Cell Carcinoma
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: TROG 12.01
  • SECONDARY ID: ACTRN12613000279729
  • NCT ID: NCT01855451

Conditions

  • HPV Positive Oropharyngeal Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
CetuximabRadiation Therapy + Cetuximab
CisplatinRadiation Therapy + Cisplatin

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Radiation Therapy + CetuximabActive ComparatorRT (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)
  • Cetuximab
Radiation Therapy + CisplatinActive ComparatorRT(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)
  • Cisplatin

Eligibility Criteria

        Inclusion Criteria:

          1. Aged 18 years or older

          2. Has provided written Informed Consent for participation in this trial

          3. Histologically confirmed squamous cell carcinoma of the oropharynx with p16 positive
             status confirmed locally by immunohistochemistry

          4. 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.

          5. 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.

          6. No prior treatment for oropharyngeal cancer

          7. Adequate haematological, renal, and hepatic function as defined by,

               1. Absolute neutrophil count (ANC, segs + bands) > /= 1.5 x 109/L

               2. Platelet count > /= 100 x 109/L

               3. Total bilirubin < /= 1.5 x upper normal limit

               4. ALT < /= 2.5 x upper normal limit

               5. Calculated creatinine clearance (Cockcroft-Gault formula) or isotopic GFR >
                  55ml/min

          8. ECOG performance status score of 0-1

          9. Participants capable of childbearing are using adequate contraception and intend to
             continue use of contraception for at least 6 months following completion of treatment

         10. Negative pregnancy test within 72 hours prior to randomisation of women who are of
             childbearing potential

         11. Suitable for follow-up for at least 24 months as per trial protocol.

         12. Sufficient proficiency in English, cognitive capacity and willingness to complete
             questionnaires

        Exclusion Criteria:

          1. History of unknown primary of the head and neck

          2. T4, N3 or distant metastases

          3. Smoking history >10 pack years with N2b or c nodal status

          4. Women who are pregnant or lactating.

          5. Previous radiotherapy to the area to be treated (excluding superficial radiotherapy
             for a cutaneous malignancy)

          6. Previous cisplatin or carboplatin chemotherapy

          7. Prior EGFR targeted therapy of any kind

          8. Primary surgery to the affected area (excisional biopsy allowed)

          9. Peripheral neuropathy > /= grade 2 (CTCAE v4.0)

         10. 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)

         11. Tinnitus > /= grade 2 (CTCAE v4.0)

         12. History of interstitial lung disease or evidence of interstitial lung disease on
             pre-registration CT

         13. 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

         14. Patients known to be HIV positive

         15. Other cancer that was diagnosed:

               1. 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

               2. 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Symptom Severity
Time Frame:20 weeks
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Symptom severity
Time Frame:24 months
Safety Issue:
Description: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).
Measure:Interference of symptoms with daily life
Time Frame:24 mths
Safety Issue:
Description: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
Measure:Psychological distress
Time Frame:36 months
Safety Issue:
Description:To compare psychological distress measured by FACT-HN domain scores and depression and anxiety scales of Hospital Anxiety and Depression Scale (HADS)
Measure:Impact on Health Related Quality of Life
Time Frame:36 months
Safety Issue:
Description:
Measure:Swallowing dysfunction
Time Frame:12 months
Safety Issue:
Description:To compare swallowing dysfunction by Functional swallowing outcome (video fluoroscopy), CTCAE (v4.0) dysphagia, MDASI and FACT questionnaires, enteral feeding rates.
Measure:Speech and dietary function
Time Frame:36 months
Safety Issue:
Description:To compare speech and dietary function as measured by the Performance Status Scale for Head & Neck Cancer Patients (PSS-HN)
Measure:Clinician-assessed acute and late toxicity
Time Frame:60 months
Safety Issue:
Description: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)
Measure:Rate of enteral feeding
Time Frame:12 months
Safety Issue:
Description:To compare rate of enteral feeding at 12 months following treatment using Barnard's exact test for the comparison of two proportions
Measure:Hearing impairment
Time Frame:24 months
Safety Issue:
Description: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).
Measure:Time to locoregional failure
Time Frame:36 months
Safety Issue:
Description:To compare time to locoregional failure primarily determined by evidence of progression or recurrence clinically or radiologically
Measure:Failure-free survival
Time Frame:36 months
Safety Issue:
Description:To compare failure-free survival by clinical and radioloigical assessments
Measure:Overall survival
Time Frame:60 months
Safety Issue:
Description:To compare overall survival by clinical assessment.
Measure:Pattern of disease failure
Time Frame:36 months
Safety Issue:
Description:Pattern of disease failure (locoregional [recurrence at primary tumour site and/or regional nodes], distant, both) as assessed radiologically.
Measure:Complete response rate
Time Frame:20 weeks
Safety Issue:
Description:To compare FDG-PET-CT complete response rate at week 20
Measure:Cost of health resource utilisation
Time Frame:24 months
Safety Issue:
Description:To compare cost of health resource utilisation via questionnaires EQ-5D-5L and RTOG return to work questionnaire.
Measure:Work status and time to return to work
Time Frame:24 months
Safety Issue:
Description:To compare work status and time to return to work by RTOG questionnaire
Measure:Potential prognostic markers
Time Frame:60 months
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Trans-Tasman Radiation Oncology Group (TROG)

Trial Keywords

  • Human Papilloma Virus
  • HPV
  • Oropharyngeal
  • Squamous Cell
  • Carcinoma

Last Updated

February 26, 2018