Phase I Trial of Dacomitinib Concomitant With Radiotherapy With and Without Cisplatin in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
- Signed written and voluntary informed consent provided.
- Patient must be willing and able to comply with scheduled visits, treatment plan,
pharmacokinetic assessments, laboratory tests and other study procedures.
- Age ≥ 18 years, male or female.
- Dose escalation phase: Arm A: patients with local or locally advanced, histologically
or cytologically confirmed SCCHN, candidates for radical radiotherapy might be
eligible. Arm B: previously untreated patients, with locally advanced, histologically
or cytologically confirmed SCCHN candidates for radical concurrent cisplatin-based
chemoradiation will be eligible.
- Dose expansion phase: previously untreated patients, with locally advanced,
histologically or cytologically confirmed SCCHN, HPV-negative determined by lack of
p16 immunohistochemical staining, candidates for radical concurrent cisplatin-based
chemoradiation will be eligible. Note: Patients with primary tumors of head and neck
in nasopharynx, skin, or unknown are excluded.
- Prior treatment with biological agents targeted to the epidermal growth factor
receptor is not allowed.
- Prior chemotherapy or radiotherapy for the treatment of the current neoplasm is not
- Patient must not have received any prior anti-neoplastic treatment within the past 2
- Any treatment-related acute toxicity, including laboratory abnormalities, must have
recovered to CTCAE Grade 1 (NCI CTCAE v.4.0) or baseline, except toxicity not
considered a safety risk. Chronic dysphagia or xerostomia or other local effect
resulting from prior surgery will not be considered an exclusion criterion.
- ECOG performance status of 0-1.
- Patient must have adequate organ function as determined by the following criteria
- Renal function: Estimated creatinine clearance of ≥ 50 mL/min using the
following formula: Creatinine clearance = [(140-age) x wt (kg) x Constant] /
creatinine (µmol/L) [Constant = 1.23 for men and 1.04 for women]
- Bone marrow function (without hematopoietic growth factors or transfusion):
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
- Liver function: Total bilirubin ≤ ULN; AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
- Cardiac function: 12-Lead electrocardiogram (ECG) with normal tracing, or
clinically non-significant changes that do not require medical intervention.
QTc interval < 480 msec, and without history of Torsades de Pointes or other
symptomatic QTc abnormality.
- Patient cannot be concurrently enrolled on another clinical trial while enrolled on
- Prior investigational drug therapy within 30 days or 5 half-lives preceding the first
dose of study medication (whichever is longer).
- Requirement for treatment with drugs that are highly dependent on CYP2D6 for
metabolism since dacomitinib is a potent CYP2D6 inhibitor in in vitro assays. [See
Appendix B: prohibited medication list; Appendix C: use with caution medication
- Patients currently taking drugs that are generally accepted to have a risk of causing
Torsades de Pointes
- Any acute or chronic medical or psychiatric condition or laboratory abnormality that
could increase the risk associated with trial participation or trial drug
administration or could interfere with the interpretation of trial results and, in
the judgment of the investigator, would make the patient inappropriate for entry in
the trial. This includes:
- History of interstitial lung disease;
- Uncontrolled hypertension, unstable angina, myocardial infarction or symptomatic
congestive heart failure within the past 12 months or serious uncontrolled
cardiac arrhythmia, diagnosed or suspected congenital long QT syndrome;
- Patients with minimally symptomatic cardiovascular (e.g. ischemic heart disease,
congestive cardiac failure, arrhythmia) or vascular disease (e.g. stroke, deep
venous thrombosis) who had anti arrhythmic therapy and/or significant changes to
medical care within 6 months to enrolment;
- Active bacterial, fungal or viral infection including hepatitis B (HBV),
hepatitis C (HCV), and human immunodeficiency virus (HIV). Serological testing
will not be required at baseline for patients who have no symptoms suggestive of
- History of significant bleeding disorder, or concurrent medications that are
felt in the opinion of the investigator to potentially lead to unacceptable
coagulation function during perioperative interval, including:
- Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease);
- Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
- Other serious uncontrolled medical disorder or active infection that would
impair the ability to receive study treatment as determined by the investigator.
- Dementia or significantly altered mental status that would limit the ability to
obtain informed consent and compliance with the requirements of this protocol.
- Female patients who are breastfeeding or pregnant are excluded. All female patients
with reproductive potential must have a negative pregnancy test (serum/urine) within
72 hours prior to starting treatment. Female patients of reproductive potential
include any female who has experienced menarche and who has not undergone successful
surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral
oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive months;
or women on hormone replacement therapy (HRT) with documented serum follicle
stimulating hormone (FSH) level >35 mL.U/mL).
- Female patients of reproductive potential or their partners must agree to use
effective contraception while receiving trial treatment and for at least 3 months
thereafter. The definition of effective contraception will be based on the judgment
of the principal investigator or designated associate.
- Inability or lack of willingness to comply with scheduled visits, treatment plans,
protocol assessments or laboratory tests.