Clinical trial NCT00424255: Study Of Adjuvant Lapatinib In High-Risk Head And Neck Cancer Subjects After Surgery
Official title: A Randomised, Double-Blind, Placebo-Controlled, Multi-centre, Phase III Study of Post-Operative Adjuvant Lapatinib or Placebo and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib or Placebo Monotherapy in High-Risk Subjects With Resected Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neoplasms, Head and Neck
Keywords: Cancer of the Head and Neck
Neck cancer
Adjuvant
Head and neck cancer
High-risk head and neck cancer
Post-surgery
Head cancer
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-01-19
Enrollment: 688
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomised, double-blind, placebo-controlled, multicentre, global Phase III trial comparing the efficacy of adjuvant oral lapatinib versus placebo in high-risk subjects with head and neck cancer following surgery. Lapatinib or placebo will be administered post-operatively in combination with chemoradiotherapy followed by maintenance with lapatinib or placebo for 1 year. The primary goal is to determine if lapatinib is effective at reducing the recurrence of the disease in these high-risk patients.

Detailed description: A Randomised, Double-Blind, Placebo-Controlled, Multi-centre, Phase III Study of Post-Operative Adjuvant Lapatinib or Placebo and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib or Placebo Monotherapy in High-Risk Subjects with Resected Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Eligibility criteria: Inclusion Criteria:

* Willing and able to sign a written informed consent.
* Histologically confirmed diagnosis of SCCHN of one of the following sites: oral cavity, oropharynx, hypopharynx and larynx.
* Pathological Stage II, III or IVa (according to AJCC cancer staging criteria \[Green, 2002\]) with no evidence of gross residual disease, and at least one of the following high risk factors by pathology:
* Extracapsular extension of nodal disease
* Positive resection margin (5 mm or less)
* Primary surgery with a curative intent completed within 4-6 weeks (and no later than 7 weeks) prior to randomization. The extent of surgical resection will follow accepted criteria for adequate excision \[Helliwell, 2005\]. Surgical margins are divided into 'mucosal' and 'deep', and for each category the resection margin (R) is classified as:
* Clear : (R0) \> 5mm.
* Close: (R1) 1 - 5mm.
* Involved: (R2) \<1mm
* Complete recovery from the surgical procedure allowing for appropriate radiotherapy. Radiation therapy is required to start as soon as adequate healing has occurred. This is normally around 4-6 weeks but no later than 9 weeks after surgery.
* Adequate tumour specimen from archived or resected tissue must be available for IHC evaluation of ErbB1 expression levels in a central laboratory and subsequent biomarker analysis.
* Male or female, between 18 and 70 years of age \[Bourhis, 2006\].

Criteria for female subjects or female partners of male subjects:

Non-child-bearing potential (i.e., a woman with functioning ovaries who has a current documented tubal ligation or hysterectomy or a woman who is menopausal); or

Child-bearing potential (i.e. a woman with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility. This category includes women with oligomenorrhoea (even severe), women who are perimenopausal and young women who have begun to menstruate), who have a negative serum pregnancy test at screening, and agree to one of the following:

Complete abstinence from intercourse from the time of the screening pregnancy test until 28 days after the final dose of test article; 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; or Oral contraceptives (either combined or progestogen only), or Injectable progestogen-only contraceptives or Implants of levonorgestrel, or Any intrauterine device with a documented failure rate of less than 1% per year; or Barrier methods (e.g. condoms, diaphragms, caps) only if used in combination with one of the above acceptable methods.

* ECOG performance status 0, 1 or 2
* Adequate haematology, renal and hepatic function Absolute neutrophil count ≥ 1,500/μL, platelets ≥ 100,000/μL Haemoglobin ≥ 9 gm/dL (5mmol/L) Calculated creatinine clearance ≥60 ml/min as determined by the modified method of Cockcroft and Gault.

Aspartate (AST) and alanine transaminase (ALT) less than 3 times the upper limit of the normal range (ULN).

Total bilirubin ≤ 2.0 mg/dL

* Left ventricular ejection fraction (LVEF) above the lower limits of the institutional normal range as measured by ECHO (if ECHO cannot be performed or if the Investigator feels it is not conclusive to evaluate LVEF, then a MUGA scan should be performed).
* Able to swallow and retain tablets whole or swallow a suspension of tablets dissolved in water at study inclusion.

The use 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 judgement of the investigator
* Current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment).

Exclusion Criteria:

* Nasopharyngeal, paranasal sinuses or nasal cavity tumours
* Head and neck cancer with histology other than squamous cell carcinoma.
* Evidence of distant metastases or gross post-operative residual disease.
* Evidence of second primary tumour.
* Any prior or current anticancer treatment of any kind - except the primary surgical resection. This will include but is not limited to: prior tyrosine kinase inhibitors, prior neoadjuvant therapy, prior radiotherapy or use of any investigational agent.
* Concurrent treatment with an investigational agent or participation in another clinical trial.
* Concurrent use of CYP3A4 inducers or inhibitors while on lapatinib/placebo. A standard 3 to 5 day course of dexamethasone for the prevention of cisplatin induced nausea and vomiting is permitted. In addition glucocorticoid daily doses (oral) 1.5mg dexamethasone (or equivalent) are allowed.
* Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure;
* Pregnant or lactating females
* 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, that was successfully treated with surgery, photodynamics or laser, will be permitted;
* Peripheral neuropathy ≥ grade 2
* Mal-absorption syndrome, disease significantly affecting GI function, or major resection of the stomach or bowel, that could affect absorption of lapatinib.
* History of allergic reactions to relevant diuretics or anti-emetics (e.g 5-HT3 antagonists) to be administered with cisplatin chemotherapy
* History of allergic reactions attributed to compounds of similar chemical composition (quinazolines) to lapatinib
* The investigator considers the subject unfit for the study as a result of the medical interview, physical examinations, or screening investigations

Primary outcomes:
measure: Disease Free Survival (DFS)
timeFrame: From randomization until the earliest date of disease recurrence or death due to any cause (average of 101 study weeks)
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: From randomization until death due to any cause (average of 131 study weeks)
measure: Disease Specific Survival (DSS)
timeFrame: From randomization until death due to head and neck cancer (average of 131 study weeks)
measure: Time to Locoregional Recurrence (TTLR)
timeFrame: From randomization until thefirst occurrence that local and/or regional recurrence is documented or the date of censor (average of 101 study weeks)
measure: Time to Distant Relapse (TTDR)
timeFrame: From randomization until the first documented occurrence that distant relapse is documented (average of 101 study weeks)
measure: Number of Participants With a Second Primary Tumor
timeFrame: From randomization until development of second primary tumor or within 28 days of first recurrence (average of 101 study weeks)
measure: Extent of Exposure
timeFrame: From randomization until end of 1year maintenance treatment (average of 63 study weeks)
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From the first dose of lapatinib/placebo until 5 days after the last dose (average of 141 study weeks)
measure: Number of Participants With the Indicated Chemistry Toxicities by Maximum Toxicity Grade (G3 and G4) at the Worst-case On-therapy Visit
timeFrame: From Baseline (within 8 weeks prior to randomization [Day 1]) until the end of the maintenance period/early withdrawal (up to Study Week 64)
measure: Number of Participants With the Indicated Hematological Toxicities by Maximum Toxicity Grade (G3 and G4) at the Worst-case On-therapy Visit
timeFrame: From Baseline (within 8 weeks prior torandomization [Day 1]) until the end of the maintenance period/early withdrawal (up to Study Week 64)
measure: Number of Participants With On-therapy and Follow-up Late Radiation Morbidity Events
timeFrame: From 180 days after completion of radiation until the last follow-up/withdrawal visit (average of 64 study weeks)
measure: Change From Baseline in Blood Pressure at the Indicated Time Points
timeFrame: Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from investigational product (IP; up to Study Week 64)
measure: Change From Baseline in Heart Rate at the Indicated Time Points
timeFrame: Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from IP (up to Study Week 64)
measure: Change From Baseline in Body Temperature at the Indicated Time Points
timeFrame: Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from IP (up to Study Week 64)
measure: Change From Baseline in Body Weight at the Indicated Time Points
timeFrame: Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of chemoradiotherapy (CRT), Maintenance Week (MW) 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, Withdrawal from IP (up to Study Week 64)
measure: Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings at the Indicated Time Points
timeFrame: Baseline (BL; within 8 weeks prior to randomization [Day 1]), End of CRT, Maintenance Week 56, Withdrawal from IP, and at any time Post-Baseline (up to Study Week 64)
measure: Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status Value
timeFrame: From Baseline (BL; within 8 weeks prior to randomization [Day 1]) until the end of the maintenance period/early withdrawal (up to Study Week 64)
measure: Change From Baseline in Quality of Life Status as Assessed by the Functional Assessement of Cancer Therapy-Head and Neck (FACT-H&N) Questionnaire
timeFrame: From randomization until the last follow-up/withdrawal visit (up to 62 study weeks)
measure: Change From Baseline in Quality of Life Status as Assessed by the EuroQol-5D (EQ-5D) Scale
timeFrame: From randomization until the last follow-up/withdrawal visit (up to 62 study weeks)
measure: Number of Participants With the Indicated Biomarker Expression Status
timeFrame: Baseline (BL; within 8 weeks prior to randomization [Day 1]) (up to Study Week 1)
measure: Number of Participants With the Indicated Worst-case On-therapy Left Ventricular Ejection Fraction (LVEF) Change From Baseline
timeFrame: From the end of the CRT until the last follow-up visit (average of 141 study weeks)
Other outcomes:
Locations:
city: Springfield
country: United States
facility: GSK Investigational Site
state: Illinois
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Lubbock
country: United States
facility: GSK Investigational Site
state: Texas
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: GSK Investigational Site
state: Santa Fe
city: Quilmes
country: Argentina
facility: GSK Investigational Site
city: Santa Fe
country: Argentina
facility: GSK Investigational Site
city: Innsbruck
country: Austria
facility: GSK Investigational Site
city: Rankweil
country: Austria
facility: GSK Investigational Site
city: Salzburg
country: Austria
facility: GSK Investigational Site
city: Vienna
country: Austria
facility: GSK Investigational Site
city: Vienna
country: Austria
facility: GSK Investigational Site
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Halifax
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: London
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: Guangzhou
country: China
facility: GSK Investigational Site
state: Guangdong
city: Wuhan
country: China
facility: GSK Investigational Site
state: Hubei
city: Beijing
country: China
facility: GSK Investigational Site
city: Beijing
country: China
facility: GSK Investigational Site
city: Fuzhou
country: China
facility: GSK Investigational Site
city: Shanghai
country: China
facility: GSK Investigational Site
city: Tianjin
country: China
facility: GSK Investigational Site
city: Zagreb
country: Croatia
facility: GSK Investigational Site
city: Zagreb
country: Croatia
facility: GSK Investigational Site
city: Brno
country: Czech Republic
facility: GSK Investigational Site
city: Olomouc
country: Czech Republic
facility: GSK Investigational Site
city: Ostrava - Poruba
country: Czech Republic
facility: GSK Investigational Site
city: Praha 8
country: Czech Republic
facility: GSK Investigational Site
city: Tallinn
country: Estonia
facility: GSK Investigational Site
city: Angers Cedex 09
country: France
facility: GSK Investigational Site
city: Annecy
country: France
facility: GSK Investigational Site
city: Caen
country: France
facility: GSK Investigational Site
city: Colmar
country: France
facility: GSK Investigational Site
city: Ferolles-Attilly
country: France
facility: GSK Investigational Site
city: La Roche sur Yon
country: France
facility: GSK Investigational Site
city: Lille
country: France
facility: GSK Investigational Site
city: Lyon
country: France
facility: GSK Investigational Site
city: Montpellier Cedex 5
country: France
facility: GSK Investigational Site
city: Paris
country: France
facility: GSK Investigational Site
city: Reims
country: France
facility: GSK Investigational Site
city: Saint Cloud
country: France
facility: GSK Investigational Site
city: Strasbourg
country: France
facility: GSK Investigational Site
city: Toulouse
country: France
facility: GSK Investigational Site
city: Villejuif Cedex
country: France
facility: GSK Investigational Site
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Karlsruhe
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Halle
country: Germany
facility: GSK Investigational Site
state: Sachsen-Anhalt
city: Dresden
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Athens
country: Greece
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Haidari, Athens
country: Greece
facility: GSK Investigational Site
city: Neo Faliro
country: Greece
facility: GSK Investigational Site
city: Peiraius
country: Greece
facility: GSK Investigational Site
city: Hong Kong
country: Hong Kong
facility: GSK Investigational Site
city: Kowloon
country: Hong Kong
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Budapest
country: Hungary
facility: GSK Investigational Site
city: Szombathely
country: Hungary
facility: GSK Investigational Site
city: Kochi
country: India
facility: GSK Investigational Site
city: Mumbai
country: India
facility: GSK Investigational Site
city: Mumbai
country: India
facility: GSK Investigational Site
city: Pune
country: India
facility: GSK Investigational Site
city: Trivandrum
country: India
facility: GSK Investigational Site
city: Galway
country: Ireland
facility: GSK Investigational Site
city: Rathgar, Dublin
country: Ireland
facility: GSK Investigational Site
city: Napoli
country: Italy
facility: GSK Investigational Site
state: Campania
city: Genova
country: Italy
facility: GSK Investigational Site
state: Liguria
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Pavia
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Venezia
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Manila
country: Philippines
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Ufa,
country: Russian Federation
facility: GSK Investigational Site
city: Bratislava
country: Slovakia
facility: GSK Investigational Site
city: Kosice
country: Slovakia
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Cordoba
country: Spain
facility: GSK Investigational Site
city: Gerona
country: Spain
facility: GSK Investigational Site
city: Granada
country: Spain
facility: GSK Investigational Site
city: Huesca
country: Spain
facility: GSK Investigational Site
city: Lerida
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Murcia
country: Spain
facility: GSK Investigational Site
city: Orense
country: Spain
facility: GSK Investigational Site
city: Santander
country: Spain
facility: GSK Investigational Site
city: Santiago de Compostela
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Zaragoza
country: Spain
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Bangkok
country: Thailand
facility: GSK Investigational Site
city: Chiangmai
country: Thailand
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: Edinburgh
country: United Kingdom
facility: GSK Investigational Site
state: Midlothian
city: Brighton
country: United Kingdom
facility: GSK Investigational Site
state: Sussex East
city: Guildford
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: 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
city: Sutton
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Harrington K, Temam S, Mehanna H, D'Cruz A, Jain M, D'Onofrio I, Manikhas G, Horvath Z, Sun Y, Dietzsch S, Dubinsky P, Holeckova P, El-Hariry I, Franklin N, Biswas-Baldwin N, Legenne P, Wissel P, Netherway T, Farrell J, Ellis C, Wang-Silvanto J, Amonkar M, Ahmed N, Santillana S, Bourhis J. Postoperative Adjuvant Lapatinib and Concurrent Chemoradiotherapy Followed by Maintenance Lapatinib Monotherapy in High-Risk Patients With Resected Squamous Cell Carcinoma of the Head and Neck: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study. J Clin Oncol. 2015 Dec 10;33(35):4202-9. doi: 10.1200/JCO.2015.61.4370. Epub 2015 Nov 2.