A Study Of Lapatinib Versus Placebo Followed By Chemoradiation In Patients With Locally Advanced Head And Neck Cancer

A Randomized, Single Blinded, Placebo-controlled, Multi-centre, Phase II Study of Lapatinib in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

This is a study comparing the activity of lapatinib versus placebo followed by chemoradiation. This study is designed to explore the effects of lapatinib monotherapy on apoptosis/necrosis, in pre-treatment and post-treatment tumour tissue samples in subjects with locally advanced squamous cell carcinoma of head and neck.

Inclusion criteria:

• Willing and able to sign a written informed consent.
• Histologically or cytologically confirmed diagnosis of SCCHN.
• Stage III, IVA and IVB disease will be eligible, who are to receive chemoradiation therapy as primary treatment (total dose ≥ 65 Gy). Subjects with distant metastases (stage IVC) will be excluded.
• Willing and able to have a tumour biopsy taken at screening and a second tumour biopsy taken during lapatinib/placebo administration.
• Male or female ≥18 years of age.

Criteria for female subjects or female partners of male subjects: Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are postmenopausal); Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhoea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or

Consistent and correct use of one of the following acceptable methods of birth control:

male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; implants of levonorgestrel; injectable progestogen; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only); or barrier methods, including diaphragm or condom with a spermicide.

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
• Subjects must have adequate haematological, renal and hepatic function. Calculated creatinine clearance ≥50 ml/min as determined by the method of Cockcroft and Gault [Cockcroft, 1976] or by the EDTA method.

Absolute neutrophil count ≥1,500/μl, platelets ≥100,000/μl. Haemoglobin ≥9gm/dL (5mmol/L). Aspartate (AST) and alanine transaminase (ALT) less than three times the upper limit of the normal range (ULN).

Total bilirubin ≤2.0 mg/dL.

• Left ventricular ejection fraction (LVEF) within the institutional normal ranges as measured by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scans.
• Able to swallow tablet whole or swallow a suspension of the tablet dissolved in water at study inclusion. If necessary, the suspension may be administered via percutaneous endoscopic gastrostomy (PEG), percutaneous jejunostomy tube (JTube), or a nasogastric tube (NG or Dobhoff type tube).
• Life expectancy of at least 6 months as judged by the investigator.

Exclusion criteria:

• Subjects with paranasal sinuses, nasopharyngeal and nasal cavity tumours;
• Subjects who have received prior systemic chemotherapy given with curative intent;
• Subjects who received prior radiotherapy;
• Prior or concurrent treatment with tyrosine kinase inhibitors;
• Use of any investigational agent within 30 days or 5 half-lives, whichever is longer, preceding the first dose of lapatinib;
• Concurrent use of CYP3A4 inducers or inhibitors;
• Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure;
• History of another malignancy within the last 5 years, with the exception of completely resected basal or squamous cell skin cancer, or successfully treated in situ carcinoma. History of non-invasive lesion or in-situ carcinoma of head and neck that was successfully treated with surgery, photodynamics or laser, will be permitted;
• Distant metastases, ie Stage IVC;
• Females or males of child-bearing potential who are sexually active, if they do not agree to practice an effective method of contraception. (For example oral contraceptives, IUD or diaphragm plus spermicide);
• Pregnant or lactating females (female patients of childbearing potential will undertake pregnancy testing at screening and during study completion/withdrawal visits);
• Malabsorption syndrome, disease significantly affecting GI function, that could affect absorption of lapatinib;
• History of allergic reactions to appropriate diuretics or antiemetics (e.g. 5-HT3 antagonists) to be administered with platinum-based chemotherapy;
• The investigator considers the patient unfit for the study as a result of the medical interview, physical examinations, or screening investigations;
• Subjects taking any prohibited medication (See Section 8.2)

Other Eligibility Criteria Considerations:

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings,precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: investigator's brochure IB and any IB supplements, and expedited investigator safety reports