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