• Response rate will be measured CT scans or MRI following every 2nd cycle of treatment.
  

• Secondary objectives will be to measure the time to progression and eventually, overall survival using CT scans taken every 2nd cycle.
  
• Safety will be assessed on an ongoing basis by monitoring side effects, adverse events, laboratory values, physical assessments.
  

This research study is being done because we have not yet been able to find the best treatment for recurrent or advanced head and neck cancer (SCCHN). Pemetrexed and gemcitabine have helped fight against SCCHN when each was given by itself. This study is different from others because it tests these two drugs together, which has not been tried before in patients with SCCHN. We will see how well these drugs can work to help to control or shrink your cancer.

We also want to find out what effects (good and bad) gemcitabine and pemetrexed have on you and your head and neck cancer. We do not know if these drugs will help you. Your cancer might get better or it might get worse. It might not have any effect on your condition. We can use what we learn from this research study to help other people with the same cancer.

Inclusion Criteria:

• Diagnosis of squamous cell cancer of the head and neck - unresectable or metastatic. Must have measurable disease by RECIST.
• Karnofsky performance status greater than or equal to 60%
• Up to one prior systemic chemotherapy, immunotherapy allowed in the advanced or metastatic setting. This does not include prior chemotherapy, immunotherapy used with radiotherapy (ie concurrent with radiation therapy or as and induction regimen pror to definitive radiation therapy).
• At least 4 weeks from prior radiation or chemotherapy, must have recovered from all acute effects of treatment.
• Adequate organ and marrow function
• Negative pregnancy test. Agree to use birth control during and for 3 months after last dose of study drug.
• At least 18 years of age.
• Sign an informed consent and HIPAA consent.
• Must be able to take and absorb enteral medication.

Exclusion Criteria:

• Serious concomitant systemic disorder that would compromise safety or ability to complete study.
• Prior treatment with gemcitabine or pemetrexed within the previous year, unless used concurrently with radiation therapy.
• Pregnancy or breastfeeding.
• Symptomatic or uncontrolled brain mets. If treated, must be off steroids for at least 2 weeks.
• Inability or unwilling to take folic acid, vitamin B12, or dexamethasone.
• Treatment within last 30 days with a drug that has not received regulatory approval for any indication.
• Inability to interrupt and NSAID or salicylate with a long half-life (piroxicam or nabumetone) for a 5 day period.
• Presence of clinically relevant third space fluid that cannot be controlled by drainage or other procedure prior to study entry.
• Active, concurrent, invasive malignancy requiring ongoing treatment.
• Corticosteroids impermissible unless for adrenal failure, septic shock or as temporizing measure for symptomatic pain, breathing, or rash.