Dacomitinib Plus Radiotherapy, With and Without Cisplatin in Patients With Squamous Cell Carcinoma of the Head and Neck
Dacomitinib Plus Radiotherapy, With and Without Cisplatin in Patients With Squamous Cell Carcinoma of the Head and Neck
This is a phase 1 study of the drug dacomitinib with radiotherapy, with or without
 chemotherapy, in patients with advanced squamous cell carcinoma of the head and neck (SCCHN).

 Dacomitinib is an oral drug, which is found to be active in SCCHN patients, blocks a receptor
 called the epidermal growth factor receptor (EGFR). By blocking signals for cancer cells to
 grow, it is believed to stop or slow the growth of tumor cells.

 The dose escalation phase will find the best dose as well as determine the safety of
 dacomitinib when given with radiotherapy and with or without chemotherapy.The dose expansion
 phase will further test the best dose determined in the dose escalation phase for response
 rate.
This is a phase 1 study of the investigational drug, dacomitinib, with radiotherapy and with
 or without chemotherapy in patients with advanced squamous cell carcinoma of the head and
 neck (SCCHN).

 There are proteins found on the surface of cells called receptors that receive signals and
 send signals to the cell to grow or to die. Dacomitinib is an oral drug that blocks a
 receptor called the epidermal growth factor receptor (EGFR) which is found to be too active
 in SCCHN patients. By blocking the signals for the cancer cells to grow, it is believed to
 stop or slow the growth of tumor cells. The treatment of SCCHN usually includes chemotherapy
 and radiation.

 The primary objectives of this study will have two phases: a dose escalation phase and a dose
 expansion phase. The dose escalation phase will find the best dose as well as determine the
 safety of dacomitinib when given with radiotherapy and with or without chemotherapy.The dose
 expansion phase will further test the best dose determined in the dose escalation phase for
 safety and response rate.

 The secondary objectives are to evaluate the pharmacokinetic properties of the combination
 therapies, and to provide preliminary survival data.
Inclusion Criteria:

 -  Signed voluntary informed consent provided.

 -  Patient willing and able to comply with visits, treatment plan, pharmacokinetics,
 laboratory tests, other study procedures.

 -  Escalation: Arm A: patients with local/locally advanced confirmed SCCHN; candidates
 for radical radiotherapy. Arm B: previously untreated patients, with locally advanced,
 confirmed SCCHN; candidates for radical concurrent cisplatin-based chemoradiation.

 -  Expansion: previously untreated patients, with locally advanced, confirmed SCCHN;
 HPV-negative candidates for radical concurrent cisplatin-based chemoradiation.Note:
 Those with primary tumors of head and neck in nasopharynx, skin, or unknown are
 excluded.

 -  Prior treatment of current neoplasm not allowed; must not have received any
 anti-neoplastic treatment within 2 years.

 -  Treatment-related toxicity must have recovered to CTCAE Grade 1 (v.4.0) or baseline,
 except toxicities not considered a risk. Chronic dysphagia, xerostomia or other effect
 resulting from prior surgery will not be considered exclusion criterion.

 -  ECOG performance status 0-1.

 -  Patient must have adequate organ function determined by: Creatinine clearance of ≥ 50
 mL/min using formula: Creatinine clearance=[(140-age) x wt (kg) x Constant]/creatinine
 (µmol/L) [Constant = 1.23 for men; 1.04 for women]. Absolute neutrophil count (ANC) ≥
 1.5 x 109/L; Leukocytes > 3.0 x 109/L; Hemoglobin > 80 g/L (or > 8 g/dL); Platelets ≥
 100 x 109/L. Total bilirubin ≤ ULN; AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN. 12-Lead
 electrocardiogram (ECG) with normal tracing, or clinically non-significant changes.
 QTc interval < 480 msec, without history of Torsades de Pointes or other QTc
 abnormality.

 Exclusion Criteria:

 -  Enrollment in another clinical trial.

 -  Prior trial drug use within 30 days or 5 half-lives preceding first dose of study
 medication.

 -  Prior treatment with agents targeted to epidermal growth factor receptor

 -  Requirement for drugs highly dependent on CYP2D6 for metabolism - dacomitinib is a
 potent CYP2D6 inhibitor [See Appendix B and C].

 -  Patients taking drugs causing risk for Torsades de Pointes

 -  Any acute/chronic medical, psychiatric, laboratory abnormality that investigator finds
 could increase risks of participation, trial drug administration or could interfere
 with trial results. Including: History of interstitial lung disease; uncontrolled
 hypertension, unstable angina, myocardial infarction, symptomatic congestive heart
 failure within a year, cardiac arrhythmia, diagnosed/suspected congenital long QT
 syndrome; cardiovascular or vascular disease with anti arrhythmic therapy and/or major
 changes to medical care within 6 months; active bacterial, fungal or viral infection
 including hepatitis B or C, and human immunodeficiency virus. Testing not required for
 patients with no symptoms of infection. History of bleeding disorder, or concurrent
 medications the investigator finds to potentially lead to unacceptable coagulation
 function, including: congenital bleeding disorders; acquired bleeding disorder within
 one year; Other serious uncontrolled medical disorder or active infection that
 investigator determines may impair ability to receive study treatment. Dementia or
 altered mental status that limits ability to obtain informed consent and compliance
 with requirements of protocol.

 -  Breastfeeding/pregnancy. Females with reproductive potential [any female who had
 menarche and who has not had successful surgical sterilization/is not postmenopausal
 (defined as amenorrhea >12 consecutive months/women on hormone replacement therapy
 with serum follicle stimulating hormone level >35 mL.U/mL)] require negative pregnancy
 test within 72 hours of treatment.

 -  Patients of reproductive potential/partners must agree to effective contraception
 while receiving trial treatment and for 3 months after. Effective contraception will
 be judgment of principal investigator or designate.

 -  Inability or lack of willingness to comply