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

OBJECTIVES:

Primary

- Evaluate the acute toxicity and feasibility of intensity modulated radiotherapy (IMRT)
in combination with radiosensitizing drugs pemetrexed disodium and erlotinib
hydrochloride in patients with recurrent or second primary squamous cell carcinoma of
the head and neck. (Phase I)

- Determine the maximum tolerated dose and recommended phase II dose of erlotinib
hydrochloride in these patients. (Phase I)

- Determine progression-free survival (PFS) at 1 year in these patients. (Phase II)

Secondary

- Determine median PFS, median overall survival (OS), and OS at 1 and 2 years in these
patients.

- Determine objective tumor response as measured by CT scan or MRI in these patients.

- Evaluate the acute and chronic toxicity of IMRT in combination with radiosensitizing
drugs pemetrexed disodium and erlotinib hydrochloride in these patients.

- Evaluate the impact of treatment on quality of life as measured by FACT-H&N, PSS-HN, MD
Anderson Dysphagia Inventory (MDADI), and swallowing by direct functional measurements
at different time points.

- Evaluate the level of phosphorylation of different tyrosine residues within the
cytoplasmic domain of EGFR, bound adaptors, as well as markers of downstream pathways
activation by nano LC-MS/MS in tumor tissue and correlate with levels of P-AKT and P-ERK
by immunohistochemistry and with response to treatment.

- Measure the levels of TS and p53 and correlate with treatment response.

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

- Phase I: Patients undergo intensity modulated radiotherapy (IMRT) once daily, 5 days a
week, for 6 weeks. Patients receive pemetrexed disodium 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 oral
erlotinib hydrochloride once daily beginning on day 1 of radiotherapy and continuing for
up to 2 years in the absence of disease progression or unacceptable toxicity.

- Phase II: Patients undergo IMRT and receive pemetrexed sodium as in phase I. Patients
also receive erlotinib hydrochloride at the maximum tolerated dose determined in phase
I.

Quality of life is assessed at baseline, weekly during treatment, at 1, 6, and 12 months, and
then annually thereafter.

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

Inclusion:

* Histologically or cytologically confirmed diagnosis of recurrent or second primary
squamous cell carcinoma (SCC) of the head and neck, including any of the following:

- Oral cavity

- Oropharynx

- Hypopharynx

- Larynx

- Recurrent neck metastases with unknown primary

Exception from pathology confirmation of tumor recurrence is accepted for patients who
originally had pathologically confirmed SCC of the Head and Neck, the new tumor is located
in the head and neck area and it is clinically considered as a recurrence of the original
tumor, and a tumor biopsy is technically difficult and would expose the patient to
unjustified risk. The treating physicians should agree and document the clinical definition
of tumor recurrence and should document the increased risk for biopsy.

- Measurable disease by CT scan or MRI OR evaluable disease

- No definitive evidence of distant metastasis

- Unresectable disease by a preliminary ENT evaluation OR refused surgery

- 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

- Has undergone prior head and neck radiotherapy (for SCC of the head and neck) to a
dose of ≤ 72 Gy that involved most of the recurrent tumor (> 75%) OR has a second
primary tumor volume in areas previously irradiated to > 45 Gy

- The entire tumor volume must be included in a treatment field that limits the total
spinal cord dose to 54 Gy (prior plus planned dose)

- Must have disease recurrence or persistence for ≥ 6 months after completion of prior
radiotherapy

- ECOG performance status 0-1

- Age ≥ 18 years

- ANC > 1,500/µL

- Platelet count > 100,000/µL

- Total bilirubin < 1.5 times upper limit of normal (ULN)

- AST/ALT < 2 times ULN

- Creatinine < 1.5 times ULN

- Willing and able to take folic acid and vitamin B12 supplementation

- Recovered from prior surgery, chemotherapy, or radiotherapy

- At least 6 months since prior radiotherapy

- At least 5 days since prior aspirin or other non-steroidal anti-inflammatory agents (8
days for long acting agents [e.g., piroxicam])

- Fertile patients must use effective contraception

Exclusion:

- Nasopharyngeal carcinoma

- Concurrent uncontrolled illness, including, but not limited to, any of the following:

- Ongoing or active infection

- Psychiatric illness or social situation that would limit compliance with study
requirements

- Significant history of uncontrolled cardiac disease (i.e., uncontrolled
hypertension; unstable angina; recent myocardial infarction [within the past 3
months]; uncontrolled congestive heart failure; or cardiomyopathy with decreased
ejection fraction)

- Active interstitial lung disease

- Presence of third space fluid that cannot be controlled by drainage

- Other concurrent investigational agents

- Pregnant or nursing

- HIV positive