Erlotinib Hydrochloride and Radiation Therapy in Stage III-IV Squamous Cell Cancer of the Head and Neck

• Time to disease progression [ Time Frame: at 6 months, every 3 months for 2 years, and then every 6 months for 2 years. ] [ Designated as safety issue: No ]
  The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started.
• Progression free survival [ Time Frame: at 6 months, every 3 months for 2 years, and then every 6 months for 2 years. ] [ Designated as safety issue: No ]
• Treatment tolerance as grade 3, 4, and 5 toxicities (NCI-CTCAE v 4.0) associated with proposed treatment [ Time Frame: screening, weekly, then q 2 months ] [ Designated as safety issue: No ]
  Compare the utility of the IADL/ADL, ECOG and KPS in predicting tolerance to treatment in patients ≥ 65 years with locally advanced (stage III or IV) squamous cell carcinoma of the head and neck who undergo treatment with erlotinib and radiation
• Overall survival [ Time Frame: at 6 months, every 3 months for 2 years, and then every 6 months for 2 years. ] [ Designated as safety issue: No ]
  The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started.
• Temporal pattern of quality of life [ Time Frame: prior to initiation of treatment, at treatment completion and twelve months following treatment completion ] [ Designated as safety issue: Yes ]
  All patients, regardless of age will complete a HRQOL assessment pretreatment.

• Lab correlates [ Time Frame: 2 yrs post concurrent chemo-radiation therapy ] [ Designated as safety issue: No ]
  Determine the effect of treatment and dose of treatment on biologic correlates in tumor tissue and/or surrounding mucosa.
• Pharmacokinetic data [ Time Frame: pre-treatment then weekly ] [ Designated as safety issue: No ]
  Determine the pharmacokinetic profile of erlotinib. Additional analyses of the pharmacokinetic data on patients receiving daily erlotinib treatment via their feeding tube will be conducted.
• Objective response rate [ Time Frame: follow for 5 years following treatment ] [ Designated as safety issue: No ]
• locoregional control rate [ Time Frame: 5 yrs following treatment ] [ Designated as safety issue: No ]
• Patterns of failure [ Time Frame: 5 yrs following treatment ] [ Designated as safety issue: No ]
• toxicities, number of persons with adverse events [ Time Frame: all timepoints in the study up to 2 yrs after treatment ] [ Designated as safety issue: Yes ]
  Safety assessments will consist of monitoring and recording protocol-defined adverse events (AEs) and serious adverse events (SAEs); measurement of protocol-specified hematology, and clinical chemistry variables; measurement of protocol-specified vital signs; and other protocol specified tests that are deemed critical to the safety evaluation of the study drug(s).
• quality of life outcomes [ Time Frame: after treatment at 6 mos ] [ Designated as safety issue: No ]
  Temporal pattern of quality of life as well as their scores on subscales will be summarized graphically; and repeated measures analysis of variance (ANOVA) will be conducted for those measures to test for changes in scores over time. The predictive value of covariates including lab correlates on quality of life will be examined by mixed models after adjusting clinical and pathological factors assuming missing values are missing at random (MAR).

• Lab correlates [ Time Frame: pre-treatment,weekly, then monthly for 2 yrs ] [ Designated as safety issue: No ]
  Determine the effect of treatment and dose of treatment on biologic correlates in tumor tissue and/or surrounding mucosa.
• Pharmacokinetic data [ Time Frame: pre-treatment then weekly ] [ Designated as safety issue: No ]
  Determine the pharmacokinetic profile of erlotinib. Additional analyses of the pharmacokinetic data on patients receiving daily erlotinib treatment via their feeding tube will be conducted.

RATIONALE: Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Erlotinib hydrochloride may also make tumor cells more sensitive to radiation therapy. Radiation therapy uses high-energy x- rays and other types of radiation to kill tumor cells. Giving erlotinib hydrochloride together with radiation therapy may be an effective treatment for patients with head and neck cancer.PURPOSE: This phase II trial is studying how well giving erlotinib hydrochloride together with radiation therapy works in treating patients with stage III-IV squamous cell cancer of the head and neck.

PRIMARY OBJECTIVES:I. To determine the time to progression of the combination of the EGFR inhibitor erlotinib and radiation therapy. SECONDARY OBJECTIVES:I. To determine objective response rate, locoregional control rate, duration of response, patterns of failure, overall survival, toxicities and quality of life outcomes of the combination of erlotinib and concurrent radiation therapy.II. To determine the pharmacokinetic profile of erlotinib. Additional analyses of the pharmacokinetic data on patients receiving daily erlotinib treatment via their feeding tube will be conducted. III. To determine the effect of treatment and dose of treatment on biologic correlates in tumor tissue and/or surrounding mucosa, EGFR expression and phosphorylation status, serum markers of angiogenic activity VEGF, sVEGFR-2, sKIT, ICAM, PDGF, fluorescence in situ hybridization (FISH) for ERBB2 for gene amplification, DNA-sequencing of EGFR and ERBB2 genes from DNA extracted from pretreatment biopsy material for mutation screening, gene expression profiling on pre-treatment biopsy material to identify predictors of response to treatment, apoptosis (TUNEL assay), Ki67 (nuclear proliferation antigen)IV. To determine the utility of the comprehensive geriatric assessment, in predicting tolerance to treatment in patients >= 65 years included in this trial. OUTLINE: Patients receive erlotinib hydrochloride orally or via gastrostomy tube once daily in weeks 1-9 and then for 2 years following completion of radiation therapy. Beginning on day 1 of week 2, patients undergo radiation therapy once daily, 5 times a week, for 5-7 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.After completion of study treatment, patients are followed up at 6 months, every 3 months for 2 years, and then every 6 months for 2 years.

• Stage III Squamous Cell Carcinoma of the Hypopharynx
• Stage III Squamous Cell Carcinoma of the Larynx
• Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity
• Stage III Squamous Cell Carcinoma of the Oropharynx
• Stage III Verrucous Carcinoma of the Larynx
• Stage III Verrucous Carcinoma of the Oral Cavity
• Stage IV Squamous Cell Carcinoma of the Hypopharynx
• Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity
• Stage IV Squamous Cell Carcinoma of the Nasopharynx
• Stage IV Squamous Cell Carcinoma of the Oropharynx
• Stage IV Verrucous Carcinoma of the Larynx
• Stage IV Verrucous Carcinoma of the Oral Cavity

• Drug: erlotinib hydrochloride
  Given orally or via gastronomy tube
  Other Names:

  • CP-358,774
  • erlotinib
  • OSI-774
  • Tarceva
• Radiation: intensity-modulated radiation therapy
  IMRT will be given in 35 fractions over 7 weeks. The primary tumor and involved nodes (PTV70) will receive 2 Gy per fractions, intermediate-risk areas (PTV63) will receive 1.8 Gy per fractions, and subclinical disease sites (PTV56) will receive 1.6 Gy perfraction. The total doses will thus be 70 Gy, 63 Gy and 56 Gy, respectively.
  Other Name: IMRT
• Other: pharmacogenomic studies
  Optional correlative studies
  Other Name: Pharmacogenomic Study
• Other: gene expression analysis
  Correlative studies
• Radiation: 3-dimensional conformal radiation therapy

  The initial target volume encompassing the gross and subclinical disease sites will receive 2.0 Gy per fraction, five fractions a week to 54 Gy in 27 fractions in 5.4 weeks. The boost volume covering gross tumor and clinically/radiologically involved nodes will receive boost irradiation for additional 16 Gy at 2.0 Gy. The primary tumor and clinically/radiologically-involved nodes will thus receive 70 Gy in 35 fractions over 7 weeks, and uninvolved upper neck nodes will receive an elective dose of 54 Gy in 5.4 weeks.

  The uninvolved lower neck nodes will receive 2.0 Gy per fraction at 3-cm depth to a total dose of 50 Gy in 25 fractions in 5.0 weeks through a matching AP or AP/PA lower neck field.

  Other Names:

  • 3D-CRT
  • conformal radiation therapy
• Other: biopsy
  Optional correlative studies
  Other Name: biopsies
• Other: pharmacological study
  Optional correlative studies
  Other Name: pharmacological studies
• Other: laboratory biomarker analysis
  Optional correlative studies
• Other: questionnaire administration
  Optional ancillary studies
• Other: enzyme-linked immunosorbent assay
  Optional correlative studies
  Other Name: ELISA
• Other: polymorphism analysis
  Optional correlative studies

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed locally advanced (stage III or IV) squamous cell carcinoma of the head and neck without distant metastatic disease, who are not candidates or have declined definitive surgical resection or for administration of standard chemotherapy during radiation therapy because of any of the following reasons: advanced age (>= 70 years); poor ECOG performance status (2 or 3); significant comorbidities, as reflected by a Charlson comorbidity index score of >= 3; abnormal hematopoietic, hepatic or renal function; patient's decision after applicable standard treatment options have been offered and declined by patient
• No prior chemotherapy, radiation therapy, or investigational antitumor drug
• Measurable disease within 4 weeks prior to registration according to the recommended RECIST response criteria
• Life expectancy of greater than 12 weeks
• Patients must have normal hepatic function or well compensated liver disease as defined by the Child-Pugh classification of severity of liver disease; patients with hepatic impairment (total bilirubin greater than upper limit of normal [ULN] or well-compensated disease [Child-Pugh class A] enrolled in the trial will be closely monitored, especially those with total bilirubin > 3 times ULN; dosage modifications (therapy interruption or discontinuation) may be necessary for severe changes in liver function; patient management will follow the FDA-approved labeling recommendations
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation
• Men and women of childbearing potential must be willing to consent to using effective contraception while on treatment and for at least 3 months thereafter
• Women of childbearing potential must have a negative pregnancy test; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• All histologies other than squamous cell carcinoma
• Salivary gland paranasal sinus and nasopharyngeal squamous cell carcinoma
• Patients who have had prior chemotherapy or radiotherapy
• Patients with metastatic disease
• Patients with ECOG performance status of 4
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ERLOTINIB
• Patients with history of any other malignancy (except squamous cell or basal cell cancer of the skin or CIS of cervix) are ineligible unless a period of 5 years has elapsed since treatment of the previous cancer and the patient is currently disease-free from the previous cancer
• Patients may not be receiving any other investigational agent
• Pregnant women; breastfeeding should be discontinued