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

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.

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