Intensity-Modulated Radiation Therapy, Pemetrexed Disodium, and Erlotinib Hydrochloride in Treating Patients With Recurrent or Second Primary Head and Neck Cancer

• Maximum tolerated dose of erlotinib hydrochloride, based on incidence of dose limiting toxicities (DLT) (phase I) [ Time Frame: Up to 6 weeks after completion of therapy ] [ Designated as safety issue: Yes ]
  DLT is defined as grade IV mucositis or dermatitis lasting more than 3 days, or grade III or IV mucositis lasting longer than 6 weeks or longer from the completion of therapy, or any other grade III or IV toxicity, regardless of duration and which do not respond to treatment or need to delay treatment for more than 2 weeks because of any type of toxicity during the re-irradiation segment of the treatment.
• Progression-free survival (PFS), defined as the percentage of patients who are alive at 1 year after beginning their concurrent re-irradiation and chemotherapy without loco-regional progression of their disease (phase II) [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  Loco-regional progression measured by CT scan or MRI using Response Evaluation Criteria in Solid Tumors (RECIST) criteria (taking as reference the smallest measurements recorded since the treatment started). PFS rate and 95% confidence intervals will be estimated.
• Overall survival [ Time Frame: Measured from the first day of chemoradiotherapy to date of death, assessed at 1 year ] [ Designated as safety issue: No ]
  Survival analysis method will also be used to estimate the median 1-year PFS and 1-year overall survival rates.
• Median progression free survival [ Time Frame: At 1 year ] [ Designated as safety issue: No ]
  Survival analysis method will also be used to estimate the median 1-year PFS and 1-year overall survival rates.
• Median progression free survival [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
• Median overall survival [ Time Frame: Measured from the first day of chemoradiotherapy to date of death, assessed at 1 year ] [ Designated as safety issue: No ]
  One-year, 2-year overall survival rates and median survival will also be compared between this protocol and the Radiation Therapy Oncology Group (RTOG) 99-11 study.
• Median overall survival [ Time Frame: Measured from the first day of chemoradiotherapy to date of death, assessed at 2 years ] [ Designated as safety issue: No ]
  One-year, 2-year overall survival rates and median survival will also be compared between this protocol and the RTOG 99-11 study.
• Overall survival [ Time Frame: Measured from the first day of chemoradiotherapy to date of death, assessed at 2 years ] [ Designated as safety issue: No ]
  One-year, 2-year overall survival rates and median survival will also be compared between this protocol and the RTOG 99-11 study.
• Objective tumor response measured by CT scan or MRI [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Quality of life as measured by speech, swallow, nutrition, and pain [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  Measure QOL by standard survey forms: FACT-H&N, PSS-HN, and swallowing by direct functional measurements and by SWAL-QOL survey. For each of these measurements, we will assess the mean and 95% confidence intervals for continuous outcomes.
• Biomarkers predictors of response and tissue prognostic markers [ Time Frame: Up to the time of tumor progression ] [ Designated as safety issue: No ]
  Evaluated by nano LC-MS/MS in tumor tissue, reported to normal tissue, the level of phosphorylation of different tyrosine residues within the cytoplasmic domain of EGFR, bound adaptors, as well as markers of downstream pathways activation and corroborate with level of P-AKT and P-ERK evaluated by immunohistochemistry and with response to treatment. Measure level of TS and P53 and corroborate with treatment response.

This phase I/II trial is studying the side effects and best dose of erlotinib hydrochloride when given together with intensity-modulated radiation therapy and pemetrexed disodium and to see how well they work in treating patients with recurrent or second primary head and neck cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as pemetrexed disodium and erlotinib hydrochloride, may make tumor cells more sensitive to radiation therapy. Erlotinib hydrochloride and pemetrexed disodium may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving intensity-modulated radiation therapy together with pemetrexed disodium and erlotinib hydrochloride may kill more tumor cells.

PRIMARY OBJECTIVES:

I. Evaluate acute toxicity and feasibility of the combined re-irradiation with radiosensitizing drugs pemetrexed (pemetrexed disodium) and erlotinib (erlotinib hydrochloride). (Phase I) II. Determine maximum tolerated dose (MTD) for erlotinib, recommended for the phase II portion of the study. (Phase I) III. Determine progression free survival at 1 year. (Phase II)

SECONDARY OBJECTIVES:

I. Median progression free survival, median overall survival and overall survival at 1 year and at 2 years.

II. Objective tumor response measured by computed tomography (CT) scan or magnetic resonance imaging (MRI).

III. Evaluate acute and chronic toxicity of the combined re-irradiation with radiosensitizing drugs pemetrexed and erlotinib.

IV. Measure quality of life (QOL) by standard survey forms: Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N), Performance Status Scale for Head and Neck Cancer Patients (PSS-HN), and swallowing by direct functional measurements and by Scale for Dysphagia-Related Outcomes Quality of Life (SWAL-QOL) survey at different time points to evaluate the impact of treatment on QOL.

V. Biomarkers evaluation by nano liquid chromatography-tandem mass spectrometry (LC-MS/MS) in tumor tissue, reported to normal tissue, the level of phosphorylation of different tyrosine residues within the cytoplasmic domain of epidermal growth factor receptor (EGFR), bound adaptors, as well as markers of downstream pathways activation and corroborate with level of phosphor (P)-AKT and phosphor-extracellular signal-regulated kinases (P-ERK) evaluated by immunohistochemistry and with response to treatment. Measure level of thymidylate synthase (TS) and P53 and corroborate with treatment response.

OUTLINE: This is a phase I, dose-escalation study of erlotinib hydrochloride followed by a phase II study.

Patients undergo intensity modulated radiotherapy (IMRT) once daily, 5 days a week, for 6 weeks. Patients receive pemetrexed disodium intravenously (IV) over 10 minutes on day 1 of radiotherapy. Treatment with pemetrexed disodium repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive erlotinib hydrochloride orally (PO) once daily (QD) beginning on day 1 of radiotherapy and continuing for up to 2 years in the absence of disease progression or unacceptable toxicity.

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

• Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma
• Recurrent Metastatic Squamous Neck Cancer With Occult Primary
• Recurrent Squamous Cell Carcinoma of the Hypopharynx
• Recurrent Squamous Cell Carcinoma of the Larynx
• Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity
• Recurrent Squamous Cell Carcinoma of the Oropharynx
• Recurrent Verrucous Carcinoma of the Larynx
• Recurrent Verrucous Carcinoma of the Oral Cavity

• Radiation: intensity-modulated radiation therapy
  Undergo radiotherapy
  Other Name: IMRT
• Procedure: quality-of-life assessment
  Ancillary studies
  Other Name: quality of life assessment
• Drug: erlotinib hydrochloride
  Given PO
  Other Names:

  • CP-358,774
  • erlotinib
  • OSI-774
• Drug: pemetrexed disodium
  Given IV
  Other Names:

  • ALIMTA
  • LY231514
  • MTA
• Other: laboratory biomarker analysis
  Correlative studies
• Other: liquid chromatography
  Correlative studies
  Other Name: LC
• Other: mass spectrometry
  Correlative studies
• Other: immunohistochemistry staining method
  Correlative studies
  Other Name: immunohistochemistry
• Genetic: protein expression analysis
  Correlative studies

Inclusion Criteria:

• Pathologically (histologically or cytologically) confirmed diagnosis of recurrent or second primary squamous cell carcinoma (SCC) of the oral cavity, oropharynx, hypopharynx, larynx, or recurrent neck metastases with unknown primary
• Disease with tumor measurable on the CT scan or MRI
• No definitive evidence of distant metastasis - not applicable for patients enrolled in the phase I, first two erlotinib dose levels
• Unresectable by a preliminary Ear, Nose, and Throat (ENT) evaluation or have refused surgery
• Prior history of head and neck radiation for head and neck squamous cell carcinoma to no more than 72 Gy and most (> 75%) of the recurrent or second primary tumor volume should be in areas previously irradiated to > 45 Gy
• Entire tumor volume must be included in a treatment field that limits the total spinal cord dose to 54 Gy (prior plus planned dose)
• Subjects must have fully recovered from the effects of any prior surgery, chemotherapy, or radiation therapy
• A minimum time period at least 6 months should have elapsed from prior radiation treatment until enrollment in the study
• Patients may have received chemotherapy as a component of their primary tumor treatment but not for recurrent or metastatic disease
• No prior treatment with systemic anti-EGFR inhibitors or pemetrexed is permitted
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) > 1,500/ul
• Platelet count > 100,000/ul
• Total bilirubin < 1.5
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than 2 times the upper limit of normal
• Creatinine < 1.5 and creatinine clearance > 45
• Subjects should be willing and able to take folic acid and vitamin B12 supplementation and should interrupt aspirin or other non-steroidal anti-inflammatory agents for a 5-day period (8-day period for long acting agents such as piroxicam) before entering the study
• Informed consent must be obtained from all subjects prior to beginning therapy
• Patients must provide verbal and written informed consent to participate in the study
• Subjects should have the ability to understand and the willingness to give verbal and sign a written informed consent document

Exclusion Criteria:

• Patients with nasopharyngeal carcinoma
• Subjects with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements, significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension, unstable angina, recent myocardial infarction [within prior 3 months], uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction)
• Patients with active interstitial lung disease
• Presence of third space fluid which cannot be controlled by drainage
• May not be receiving any other investigational agents
• Pregnant women
• Breastfeeding should be discontinued
• Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy
• Men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control
• Subjects who are women of childbearing potential and sexually active males must be willing to use effective contraception while on study
• All women of child bearing potential (WOCBP) should be instructed to contact the investigator immediately if they suspect they might be pregnant
• Human immunodeficiency virus (HIV)-positive subjects are excluded from the study