Cetuximab and Dasatinib in Recurrent Squamous Cell Carcinoma

• Time to progression [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  To estimate time to progression and overall survival.
• The maximum toxicity for each category of interest in each subject [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  To evaluate the safety of the combination of dasatinib (D) and cetuximab (C) in this patient population. The maximum toxicity for each category of interest will be recorded for each patient and the summary results will be presented in tabular form.

This is a single-arm, non-masked, open-label, Phase II study of cetuximab + dasatinib in recurrent Squamous Cell Carcinoma of The Head and Neck (SCCHN) that has recurred after cetuximab-containing therapy (please see attached schema).

The primary endpoint is ORR. Progression and response will be assessed by RECIST. Patients will continue until PD or intolerable toxicity. Exploratory laboratory correlates are described below.

Patients must have recurrent SCCHN and may have received any number of prior palliative systemic therapies for recurrent disease (without cetuximab or othr EGFR inhibitor). One prior curative regimen (induction, primary or postoperative chemoradiotherapy) should have been given AND all patients should have been exposed to cetuximab as part of prior potentially curative treatment (i.e. with radiotherapy or induction therapy). The last cetuximab dose should be > 3 months. Those who have received a prior Src kinase inhibitor or EGFR inhibitor other than cetuximab are not eligible.

• Drug: Cetuximab
  Cetuximab 250 mg/m2 IV weekly after loading dose 400 mg/m2 on cycle 1, day 1
  Other Name: Erbitux
• Drug: Dasatinib
  Dasatinib 150 mg po

Inclusion Criteria:

• Patients must have recurrent SCCHN that has been previously treated with cetuximab as part of potentially curative therapy (i.e. with induction therapy, radiotherapy or chemoradiotherapy). The interval from completion of cetuximab and study treatment should be >3 months.
• Measurable disease per RECIST 1.1.
• One prior curative regimen (induction, primary or postoperative chemoradiotherapy) should have been given AND all patients should have been exposed to cetuximab as part of prior potentially curative treatment (i.e. with radiotherapy or induction therapy). The last cetuximab dose should be > 3 months.
• Unlimited prior treatment with radiation or chemoradiotherapy
• Any number of prior regimens for recurrent or metastatic SCCHN (i.e. palliative treatment) but without cetuximab or another EGFR inhibitor
• Age > or equal to 18 years
• ECOG performance status < or equal to 2
• Life expectancy of greater than 12 weeks.
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count > or equal to 1,200/µL
• platelets > or equal to 100,000/µL
• total bilirubin within normal institutional limits
• AST(SGOT)/ALT(SGPT) < or equal to 2.5 X institutional upper limit normal
• Creatinine up to 1.5 X normal institutional limits
• Ability to understand and the willingness to sign a written informed Consent document.
• Patients should not be taking concomitant medication that are CYP3A4 inducers or potent inhibitors (+++) and should try to avoid taking proton pump inhibitors and H2 antagonists during rest of treatment period. The above medications will be continued only if medically necessary and their use will be noted.
• Sexually active women of childbearing potential must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. In addition, 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. All WOCBP MUST have a negative pregnancy test prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. In addition, all WOCBP should be instructed to contact the Investigator immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during study participation.

Exclusion Criteria:

• Prior treatment with an EGFR inhibitor other than cetuximab at any time
• Prior treatment with an EGFR inhibitor as part of a regimen for recurrent or metastatic SCCHN.
• Prior treatment with SFK inhibitor at any time
• Patients who have not recovered from adverse events due to prior agents. A minimum interval of 3 weeks should have elapsed from prior radiotherapy and/or chemotherapy
• Patients may not have received an investigational agent within 4 weeks of starting this trial.
• Patients with untreated brain metastases should be excluded from this clinical trial
• History of allergic reactions to monoclonal antibodies.
• Inability to swallow oral medications (unless patients use a feeding tube in which case they are eligible).
• Uncontrolled angina or uncontrolled hypertension or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).
• Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) on the Bazett's correction.
• Diagnosed or suspected congenital long QT syndrome.
• Patients currently taking drugs that are generally accepted to have a risk of causing Torsades de Pointes including: quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide, erythromycins, clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
• Any other uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, or psychiatric illness/social situations that would limit compliance with study requirements.
• History of significant bleeding disorder unrelated to cancer, including: diagnosed congenital bleeding disorders (e.g., von Willebrand's disease), diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies).