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Phase III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer

Phase 3
18 Years
Open (Enrolling)
Head and Neck Cancer, Precancerous Condition

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Trial Information

Phase III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer



- To determine whether substitution of cisplatin with cetuximab will result in comparable
5-year overall survival.


- To monitor and compare progression-free survival for "safety".

- To compare patterns of failure (locoregional vs distant).

- To compare acute toxicity profiles (and overall toxicity burden).

- To compare overall quality of life (QOL) short-term (< 6 months) and long-term (2

- To compare QOL Swallowing Domains short-term and long-term.

- To compare clinician-reported versus patient-reported CTCAE toxicity events.

- To explore differences in the cost effectiveness of cetuximab as compared to cisplatin.

- To explore differences in work status and time to return to work.

- To compare patient-reported changes in hearing.

- To compare CTCAE v. 4 late toxicity at 1, 2, and 5 years.

- To evaluate the effect of tobacco exposure (and other exposures) as measured by
standardized computer-assisted self interview (CASI) on overall survival and
progression-free survival.

- To pilot CASI collection of patient reported outcomes in a cooperative group setting.

- To determine whether specific molecular profiles are associated with overall or
progression-free survival.

- To investigate associations between changes in serum biomarkers or HPV-specific
cellular immune responses measured at baseline and three months with overall or
progression-free survival.

OUTLINE: This is a multicenter study. Patients are stratified according to T stage (T1-2 vs
T 3-4), N stage (N0-2a vs N2b-3), Zubrod performance status (0 vs 1), and smoking history (≤
10 pack-years vs > 10 pack-years). Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients undergo image-guided intensity-modulated radiation therapy (IMRT) once
daily on days 1-4 and twice daily on day 5 weekly for 6 weeks. Patients also receive
high-dose cisplatin IV over 1-2 hours on days 1 and 22.

- Arm II: Beginning 1 week prior to IMRT, patients receive cetuximab IV over 2 hours.
Patients then receive cetuximab IV over 1 hour once weekly for 7 weeks. Patients
undergo IMRT as in arm I.

Tumor tissue and blood samples are collected at baseline and may also be collected at 3- and
6-month follow-up visits for correlative studies.

Patients may complete quality-of-life questionnaires and risk factors for head and neck
cancer surveys at baseline, periodically during study, and at follow-up for 1 year.

After completion of study therapy, patients are followed up at 1-3 months, every 3 months
for 2 years, every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria


- Pathologically (histologically or cytologically) proven diagnosis of squamous cell
carcinoma (including the histological variants papillary squamous cell carcinoma and
basaloid squamous cell carcinoma) of the oropharynx (tonsil, base of tongue, soft
palate, or oropharyngeal walls)

- No cancer from an oral cavity site (oral tongue, floor mouth, alveolar ridge,
buccal, or lip), nasopharynx, hypopharynx, or larynx, even if p16 positive

- No carcinoma of the neck of unknown primary site origin (even if p16 positive)

- Cytologic diagnosis from a cervical lymph node is sufficient in the presence of
clinical evidence of a primary tumor in the oropharynx

- Clinical evidence should be documented; may consist of palpation, imaging,
or endoscopic evaluation; and should be sufficient to estimate the size of
the primary (for T stage)

- No distant metastasis or adenopathy below the clavicles

- Patients must be positive for p16, determined by the OSU Innovation Center CLIA lab
prior to step 2 registration (randomization)

- Paraffin-embedded cytology specimens are acceptable for p16 evaluation, but
cytology smears are not

- Patients must have clinically or radiographically evident measurable disease at the
primary site or at nodal stations

- Tonsillectomy or local excision of the primary without removal of nodal disease
is permitted, as is excision removing gross nodal disease but with intact
primary site

- Limited neck dissections retrieving ≤ 4 nodes are permitted and considered as
non-therapeutic nodal excisions

- Fine-needle aspirations of the neck are insufficient due to limited tissue for
retrospective central review

- Biopsy specimens from the primary or nodes measuring at least 3-5 mm are

- Clinical stage T1-2 N2a-N3 or T3-4 any N, including no distant metastases

- No clinical stage T1-2 N0-1

- No simultaneous primaries or bilateral tumors


- Zubrod performance status 0-1

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin (Hgb) ≥ 8.0 g/dL (transfusion or other intervention to achieve Hgb ≥ 8.0
g/dL is acceptable)

- Bilirubin ≤ 2 mg/dL

- AST or ALT ≤ 3 times upper limit of normal

- Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min

- Negative pregnancy test

- Women of childbearing potential and male participants must agree to use a medically
effective means of birth control throughout their participation in the treatment
phase of the study, and until at least 60 days following the last study treatment

- Patients who are HIV-positive and have no prior AIDS-defining illness and have CD4
cells of at least 340/mm³ are eligible

- HIV status must be known prior to registration

- No multidrug resistance for HIV infection

- Not seropositive for hepatitis B (hepatitis B surface antigen positive or
anti-hepatitis B core antigen positive) or hepatitis C (anti-hepatitis C antibody

- Immunity to hepatitis B (anti-hepatitis B surface antibody positive) allowed

- No prior invasive malignancy except non-melanoma skin cancer, or malignancy for which
the patient has been disease-free for at least 3 years (e.g., carcinoma in situ of
the breast, oral cavity, or cervix)

- No severe, active co-morbidity, defined as any of the following:

- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 6 months

- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- Transmural myocardial infarction within the last 6 months

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days of

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- Laboratory tests for liver function and coagulation parameters are not
required for entry into this protocol

- Immunocompromised patients

- No prior allergic reaction to cisplatin or cetuximab


- See Disease Characteristics

- No prior systemic chemotherapy for the study cancer

- Prior chemotherapy for a different cancer allowed

- No prior radiotherapy to the region of the study cancer that would result in overlap
of radiation therapy fields

- No prior cetuximab or other anti-EGFR therapy

- No concurrent amifostine as a radioprotector

- No concurrent granulocyte colony-stimulating factor or erythropoietin

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

5-year overall survival

Safety Issue:


Principal Investigator

Andy M. Trotti, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute



Study ID:




Start Date:

June 2011

Completion Date:

Related Keywords:

  • Head and Neck Cancer
  • Precancerous Condition
  • stage III squamous cell carcinoma of the oropharynx
  • stage IV squamous cell carcinoma of the oropharynx
  • human papilloma virus infection
  • Head and Neck Neoplasms
  • Precancerous Conditions
  • Oropharyngeal Neoplasms



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