Clinical trial NCT00387127: Lapatinib Versus Placebo Given Concurrently With Cisplatin And Radiotherapy In Patients With Unresected Head And Neck Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neoplasms, Head and Neck
Keywords: Neck Cancer
Locally advanced head and neck cancer
locally advanced
Head and Neck cancer
lapatinib
EGFR/ErbB2 inhibitor
Head Cancer
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-10-12
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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;

Primary outcomes:
measure: Number of Participants (Par.) With Complete Response (CR), as Assessed by Independent Radiological Review
timeFrame: From the date of randomization until 6 months post chemoradiation treatment, assessed for a median time of 13 months
Secondary outcomes:
measure: Number of Participants With CR, as Assessed by the Investigator
timeFrame: From the date of randomization until 6 months post chemoradiation treatment, assessed after a median time of 13 months of follow-up
measure: Progression-Free Survival (PFS), as Assessed by the Investigator
timeFrame: From the date of randomization until the date of disease progression or death due to any cause, assessed after a median of 22 months of follow-up
measure: Overall Survival (OS)
timeFrame: From the date of randomization until the date of death due to any cause, assessed after a median of 30.9 months
measure: Number of Participants Who Died Due to Progressive Disease
timeFrame: From the date of randomization until the date of death due to disease under study, assessed after a median of 30.9 months
measure: Disease-specific Survival
timeFrame: From the date of randomization until the date of death due to disease, assessed after a median of 13 months of follow-up
measure: Number of Participants With Loco-regional Recurrence of Initial Disease
timeFrame: From the date of randomization until progression in the T or N site or death due to any cause, assessed after a median of 30.9 months
measure: Loco-regional Control
timeFrame: From the date of randomization until progression in the T or N site or death due to any cause, assessed after a median of 30.9 months
measure: Number of Participants With Distant Recurrence of Initial Disease
timeFrame: From the date of randomization until the first occurrence of distant metastasis, assessed after a median of 30.9 months
measure: Distant Relapse
timeFrame: From the date of randomization until the first occurrence of distant metastasis, assessed after a median of 30.9 months
measure: Number of Participants With Overall Response (OR), as Assessed by the Investigator
timeFrame: From the date of randomization until 6 months post chemoradiation treatment, assessed for a median of 13 months
measure: Number of Participants Positive and Negative for the Expression of Biomarkers in Tumor Tissue: Human Epidermal Growth Factor Receptor (HER)-1, HER2, HER3, HER4, P16, and Transforming Growth Factor (TGF-alpha)
timeFrame: Up to 28 days prior to the date of the first dose of lapatinib/placebo start
measure: Plasma Proteome Analysis
timeFrame: From up to 28 days prior to the first dose of lapatinib/placebo start to 8 weeks after the first dose
measure: Analysis of Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) From Tumor Samples
timeFrame: Screening
measure: Number of Participants Negative and Positive for Human Papilloma Virus (HPV) Infection, as Determined From Tumor Samples
timeFrame: Up to 28 days prior to the first dose of lapatinib/placebo
measure: Number of Participants Positive and Negative for Biomarker HER1/ErbB1 Categorized in the Indicated Independent Review Panel-assessed Tumor Responses by Expression of Biomarkers From Tumor Tissue: Sensitivity Analysis - 0 Versus (1, 2, 3)
timeFrame: From the date of randomization until 6 months post chemoradiation treatment, assessed for up to 24 weeks
measure: Number of Participants Positive and Negative for Biomarker HER1/ErbB1 Categorized in the Indicated Independent Review Panel-assessed Tumor Responses by Expression of Biomarkers From Tumor Tissues: Sensitivity Analysis - 0, 1, 2 Versus 3
timeFrame: From the date of randomization until 6 months post chemoradiation treatment, assessed for up to 24 weeks
Other outcomes:
measure: Number of Participants Classified as Responders, as Per Volumetric Tumor Response
timeFrame: From the date of randomization until 6 months post chemoradiation treatment, assessed for a median of 13 months
Locations:
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Kansas City
country: United States
facility: GSK Investigational Site
state: Missouri
city: Charlotte
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Lens
country: France
facility: GSK Investigational Site
city: Lille
country: France
facility: GSK Investigational Site
city: Lyon
country: France
facility: GSK Investigational Site
city: Paris cedex 15
country: France
facility: GSK Investigational Site
city: Vandoeuvre-Les-Nancy
country: France
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Győr
country: Hungary
facility: GSK Investigational Site
city: Ahemdabad
country: India
facility: GSK Investigational Site
city: Mumbai
country: India
facility: GSK Investigational Site
city: Thiruvananthapuram
country: India
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Leiden
country: Netherlands
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Lima
country: Peru
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
city: Northwood
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
city: Coventry
country: United Kingdom
facility: GSK Investigational Site
city: Leeds
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle upon Tyne
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Harrington K, Berrier A, Robinson M, Remenar E, Housset M, de Mendoza FH, Fayette J, Mehanna H, El-Hariry I, Compton N, Franklin N, Biswas-Baldwin N, Lau M, Legenne P, Kumar R. Randomised Phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease. Eur J Cancer. 2013 May;49(7):1609-18. doi: 10.1016/j.ejca.2012.11.023. Epub 2012 Dec 19.
citation: Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol. 2014 Nov;25(11):2101-2115. doi: 10.1093/annonc/mdu265. Epub 2014 Jul 23.