A Study of Dasatinib, Cetuximab and Radiation With or Without Cisplatin in HNSCC
Condition: Head and Neck Cancer
MeSH terms: Head and Neck Neoplasms
Intervention: Cetuximab; Dasatinib; Cisplatin; Radiation Therapy
Intervention description: single agent cetuximab loading dose of 400mg/m2 on day1, cetuximab maintenance dose 250mg/m2 on day 8; Oral Dasatinib Days 8 through 64.; Q 3 weeks (Days 15, 36 and 57): +/- 3 Days; Standard Radiation Therapy.
Intervention MeSH terms: Cisplatin; Cetuximab; Dasatinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 22.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: HNSCC; Dasatinib; Cetuximab; Cisplatin

Summary:

      Primary Objective for Phase I

        1. To determine the maximally tolerated dose (MTD) of daily Oral dasatinib in combination
           with cetuximab/RT in Cohort A.

        2. To determine the MTD of daily oral dasatinib in combination with cisplatin/cetuximab/RT
           in Cohort B
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patients must have a histologically confirmed operable or inoperable squamous cell
             carcinoma of OC, OP, HP, or larynx prior to proceeding with treatment.

          2. Patients must be AJCC stage II (T2N0) or III (T1-2N1) of oral cavity, oropharynx, only
             T2N0 of hypopharynx, T2N0-1 supraglottic laryngeal cancers (AJCC Fifth Edition, 1997)
             for Arm A of the study, and must be AJCC stage III (T3N0-1) or IV (T1-4N2-3M0,
             T4N0-1M0) oral cavity, oropharynx, hypopharynx, glottic and supraglottic laryngeal
             cancers for Arm B of the study.

          3. Patients must have measurable disease,.

          4. Subject, age ≥ 18 years.

          5. Performance Status (ECOG) 0-1

          6. No previous therapy for the tumor, including chemotherapy, radiation therapy,
             immunotherapy, EGFR targeted therapy, src directed therapies or investigational
             agents.

          7. Adequate Organ Function.

               -  Total bilirubin ≤ 1.5 x ULN

               -  AST and ALT ≤ 2.5 x ULN

               -  Alkaline phosphatase ≤ 2.5 x ULN

               -  Hepatic enzymes (AST, ALT) ≤ 2.5 times the institutional ULN.

               -  Serum Na, K+, Mg2+, Phosphate and Ca2+ ≥ lower limit of normal (LLN).

               -  Serum Creatinine clearance ≥ 60 ml/min.

               -  Hemoglobin, neutrophil count, platelets, PT, PTT all Grade 0-1.

               -  ANC ≥ 1,500/mL

               -  Platelets ≥ 100,000 mL

          8. Concomitant medications

               -  Patient agrees to discontinue St. Johns Wort, proton pump inhibitors, H2
                  blockers, aspirin and NSAIDS while receiving dasatinib therapy.

               -  Patient agrees that IV and po bisphosphonates will be withheld for the first 8
                  weeks of dasatinib therapy due to risk of hypocalcemia.

          9. Women of childbearing potential (WOCBP) must have:

             - A negative serum or urine pregnancy test (sensitivity ≤ 25IU HCG/L) within 72 hours
             prior to the start of study drug administration.

         10. Persons of reproductive potential must agree to use and utilize an adequate method of
             contraception throughout treatment and for at least 4 weeks after study drug is
             stopped.

         11. Ability to understand and willingness to sign a written informed consent, including a
             HIPAA form according to institutional guidelines.

        Exclusion Criteria:

          1. Any prior radiation above the clavicles

          2. Prior head and neck cancer. Any other prior invasive malignancy if disease free
             interval is ≤ 3 years. Nonmelanomatous carcinomas of the skin and in situ cervical
             dysplasia are allowed if completely resected within three year interval or can be
             completely resected prior to starting treatment.

          3. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to cetuximab, dasatinib or other agents used in study.

          4. Gastrointestinal tract disease resulting in an inability to take or absorb oral or
             enteral medication.

          5. Concurrent medical condition which may increase the risk of toxicity, including:

               -  Pleural or pericardial effusion of any grade.

               -  Cardiac Symptoms; any of the following should be considered for exclusion:

               -  Uncontrolled angina, congestive heart failure or MI within (6 months).

               -  Diagnosed congenital long QT syndrome.

               -  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).

          6. Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to
             protocol treatment.

          7. 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).

               -  Ongoing or recent (≤ 3 months) significant gastrointestinal bleeding.

          8. Concomitant Medications, any of the following should be considered for exclusion:

               1. Category I drugs that are generally accepted to have a risk of causing Torsades
                  de Pointes including: (Patients must discontinue drug 7 days prior to starting
                  dasatinib) quinidine, procainamide, disopyramide amiodarone, sotalol, ibutilide,
                  dofetilide erythromycin, clarithromycin chlorpromazine, haloperidol,
                  mesoridazine, thioridazine, pimozide cisapride, bepridil, droperidol, methadone,
                  arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine,
                  sparfloxacin, lidoflazine.

               2. The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is
                  not recommended. The use of antacids should be considered in place of H2 blockers
                  or proton pump inhibitors in patients receiving dasatinib therapy. If antacid
                  therapy is needed, the antacid dose should be administered at least 2 hours prior
                  to or 2 hours after the dose of dasatinib.

          9. Patient may not be receiving any prohibited CYP3A4 inhibitors. Refer to section 10 for
             other concomitant medications you may wish to prohibit based on disease/patient
             population.

         10. Women who:

               -  are unwilling or unable to use an acceptable method to avoid pregnancy for the
                  entire study period and for at least 4 weeks after cessation of study drug, or

               -  have a positive pregnancy test at baseline, or

               -  are pregnant or breastfeeding

         11. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
             treatment of either a psychiatric or physical (e.g., infectious) illness.