Inclusion Criteria:

• Patients must have histologically or cytologically confirmed advanced or metastatic head and neck squamous cell (HNSCC) cancer not amenable to potentially curative resection.
• Tumor must be amenable to sequential biopsies, and patients must be willing to undergo 3 sequential tumor biopsies.
• Patients must have evidence of progression after first-line chemotherapy for locally advanced or recurrent disease. There has to be at least a 4-week period since the last administration of prior therapy and initiation of the current study drugs.
• Cetuximab is indicated. However, prior therapy with cetuximab (particularly if in the primary setting) is allowed.
• Presence of measurable target on a CT-scan available for external review, with at least one diameter >/= 2cm (>/= 1cm if spiral CT-scan is used for assessment and follow-up).
• Age >/= 18 years.
• ECOG performance status <2 (Karnofsky >60%, see Appendix A).
• Life expectancy greater than 12 weeks.
• Patients must have normal organ and marrow function as defined below:
• leukocytes >3,000/μl
• absolute neutrophil count >1,500/μl
• platelets >100,000/μl
• total bilirubin <1.5xULN
• AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal
• creatinine <1.5xULN OR
• creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine above ULN.
• The effects of IPI-926 or cetuximab on the developing human fetus are unknown. All women of child-bearing potential (WCBP), all sexually active male patients, and all partners of patients must agree to use adequate methods of birth control throughout the study. Women of child-bearing potential (defined as being less than 1 year post-menopausal) must have a negative serum or urine β human chorionic gonadotropin (βhCG) pregnancy test; and men and women of reproductive potential must agree to practice an effective method of avoiding pregnancy while receiving study drug and for 30 days after the final dose of study drug. Effective contraception includes use of oral contraceptives with an additional barrier method, double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive foam), Depo-Provera, partner vasectomy, and total abstinence.
• Ability to understand and the willingness to sign a written informed consent document.
• Both men and women of all ethnic groups are eligible for this trial.

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Patients receiving any other investigational agents.
• Patients with known brain metastases.
• History of allergic reactions (as determined by the treating physician) attributed to cetuximab or compounds of similar chemical or biologic composition to IPI-926.
• Patients taking any mediation listed in section 4.4 [Concomitant medications]. Briefly, patients taking rifampin, St. John's wort, carbamazepine, phenytoin, and phenobarbital are excluded from this trial.
• Uncontrolled intercurrent illness including, but not limited to, hypertension, ongoing or active infection, bleeding diathesis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Baseline QTcF >450 msec in men or >470 msec in women.
• Concurrent treatment with any agent known to prolong the QTc interval (see Appendix 9).

• Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation and meet any of the following criteria are excluded:

  • Have been on a stable dose of anticoagulation for <1 month
  • Have had a Grade 2, 3 or 4 hemorrhage in the past month
  • Are experiencing continued symptoms from their venous thromboembolic event

Patients who have had a venous thromboembolic event but do not meet any of the above three criteria are eligible for participation.

• History of a seizure within the last 10 years or seizure disorder requiring anti-epileptic medications.
• Patients must not have any problems interfering with the ability to swallow tablets.
• Known HIV-positive patients.
• IPI-926 is predominantly metabolized by the CYP 3A4 enzyme in the liver. The possible clinical effects that inhibitors or inducers of CYP 3A4 may have on IPI-926 is unknown. Therefore, patients taking potent inhibitors or inducers of CYP 3A4 should not be enrolled on this study.
• Presence of active infection or systemic use of antibiotic within 72 hours of treatment
• Cirrhotic liver disease, ongoing alcohol abuse, or known chronic active or acute hepatitis