Lapatinib Versus Placebo Given Concurrently With Cisplatin And Radiotherapy In Patients With Unresected Head And Neck Cancer

A Randomized, Double-blind, Placebo Controlled, Multicentre, Phase II Study of Oral Lapatinib in Combination With Concurrent Radiotherapy and Cisplatin Versus Radiotherapy and Cisplatin Alone, in Subjects With Stage III, IVA, B Squamous Cell Carcinoma of the Head and Neck (SCCHN)

This is a phase II study comparing the effects of lapatinib versus placebo when administered concurrently with cisplatin and radiotherapy followed by 1 year monotherapy with lapatinib or placebo. The study is designed to evaluate and compare the two treatment groups with respect to complete response rate at 6 months following chemoradiation completion.

Inclusion criteria:

• Willing and able to sign a written informed consent;
• Histologically confirmed diagnosis of SCCHN of one or more of the following sites:

oral cavity, oropharynx, hypopharynx and larynx;

Multiple primary tumours will:

Have to be histologically proven; Have to be anatomically distant and surrounded by normal tissue; Exclude distant metastasis.

• Prior to enrolment subjects must have ErbB1 over-expression determined by immunohistochemistry (IHC) 3+ as assessed by a central laboratory;
• Subjects with stage III and IVA/IVB disease, who are to receive cisplatin chemotherapy and radiation therapy as primary treatment (total dose 65 - 70 Gy); Subjects with any Tis, T1 or T2 disease regardless of N stage, are excluded. Subjects with distant metastases, ie Stage IVC, are excluded.
• Willing and able to have a tumour biopsy taken at screening; For patients who have had prior tumour biopsy, an adequate archived specimen must be available.
• 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 GM2005/00448/00 CONFIDENTIAL EGF105884 22 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.

• 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 modified method of Cockcroft and Gault 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 4 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) scan;
• Able to swallow tablets whole or swallow a suspension of tablets dissolved in water at study inclusion; The use and timing of feeding tube is optional. If necessary, the suspension may be administered via percutaneous endoscopic gastrostomy (PEG), percutaneous jejunostomy tube (J- Tube), or a nasogastric tube (NG or Dobhoff type tube).
• Life expectancy of at least 6 months in the best judgment of the investigator.

Exclusion criteria:

• Nasopharyngeal, paranasal sinuses or nasal cavity tumours;
• Any prior or current treatment for invasive head and neck cancer of any kind. This will include but is not limited to: prior tyrosine kinase inhibitors, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent;
• Concurrent use of CYP3A4 inducers or inhibitors. A standard 3-day course of dexamethasone for the prevention of cisplatin-induced nausea and vomiting is permitted;
• 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, including in the head and neck region that was successfully treated with surgery, photodynamics or laser, will be permitted;
• Peripheral neuropathy ≥ grade 2;
• Pregnant or lactating females (female subjects of child-bearing 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 antiemetics (e.g. 5-HT3 antagonists) to be administered with platinum chemotherapy;
• The investigator considers the subject unfit for the study as a result of the medical interview, physical examinations, or screening investigations;