EGF102988

GlaxoSmithKline

980 Great West Road, Brentford, Middlesex, United Kingdom,

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

No

No

No

Final

14 Mar 2014

No

Yes

15 Nov 2013

No

To evaluate and compare DFS from randomisation to the end of the study in high-risk subjects with resected stage III or IVa SCCHN treated with adjuvant placebo or lapatinib and chemoradiotherapy followed by maintenance placebo or lapatinib for 1 year.

- Cardiac monitoring: an ECHO scan (or MUGA scan) was performed at screening, at the end of the CRT period and every 8 weeks during the maintenance phase. For subjects who had a decreased LEVF during the CRT and/or maintenance period, the ECHO or MUGA scans were performed in the follow-up period. - Liver chemistry monitoring and follow-up criteria were implemented in order to follow up on any potential hepatobiliary disorders that may occur. Hepatic function was to be monitored every 4 weeks during treatment and stopping rules were defined for severe hepatic events. - An IDMC (Independent Data Monitoring Committee) convened to review accumulating safety (every six months) and efficacy (DFS) (only at pre-planned interim, futility analysis) data and to provide an opportunity to terminate the study early in case of any concerns regarding safety and/or efficacy. - Modification of the Timing of the primary analysis: with the plateauing of investigator observed DFS events, it was decided to conduct the primary analysis with fewer events than originally planned and to discontinue DFS assessments to reduce burden and exposure to invasive tests and scans for patients still in DFS follow-up. Upon approval of amendment 04, patients on DFS follow-up moved to survival follow-up. . - Regarding compliance and study medication administration, subjects were allowed to take tablets as a suspension, in recognition of the particular difficulty some patients affected by SCCHN and its treatment could experience in swallowing tablets. - Diarrhea Management guidelines/ recommendation were provided to Investigators to help managing any potential diarrhea AE - Radiotherapy (RT) Quality Assurance program: in order to standardize RT practice an independent vendor qualified each site, provided RT guidelines, and reviewed the RT plan for every subject.

21 Dec 2006

No

Yes

Slovakia: 24

United Kingdom: 21

Austria: 15

Czech Republic: 29

Estonia: 1

France: 116

Germany: 51

Greece: 21

Hungary: 41

Italy: 17

Argentina: 9

Canada: 3

China: 80

Croatia: 18

Hong Kong: 8

India: 119

Philippines: 14

Russian Federation: 40

Spain: 36

Thailand: 22

United States: 3

688

390

0

0

0

0

0

0

611

77

0

Overall Study (overall period)

Randomised - controlled

Yes

Placebo

Tablet

Oral use

6 tablets daily (1500 mg per day) one hour before or one hour after the morning meal

Lapatinib

Tablet

Oral use

6 tablets daily (1500 mg per day) one hour before or one hour after the morning meal

Cisplatin

Solution for infusion

Intravenous use

Administered intravenously at a dose of 100mg/m2 on approximately days 1, 22 and 43 of radiotherapy (approximately study days 8, 29 and 50). Standard hydration therapy and anti-emetic prophylaxis (including dexamethasone) will be administered as per institutional standard of care.

Placebo

Lapatinib 1500 mg

Placebo

Lapatinib 1500 mg

Lapatinib 1500 mg

Participants received lapatinib 1500 mg per oral monotherapy QD for 1 week, followed by radiotherapy of 2 Gy per day for 5 days per week (for a total of 66 Gy for up to 7 weeks). Participants received concurrent cisplatin 100 mg/m^2 IV on Days 1, 22, and 43 of radiotherapy. One week prior to the start of chemoradiotherapy, then concurrently for 6 to approximately 7 weeks with chemoradiotherapy, participants received lapatinib 1500 mg per oral administration QD, followed by maintenance lapatinib 1500 mg per oral monotherapy QD for up to 1 year or until evidence of disease relapse, whichever was sooner.

DFS is defined as the time from randomization until the earliest date of disease recurrence (evidence of local, regional, or distant disease progression, second primary tumor) or death due to any cause. Disease recurrence was based on the assessments from the blinded, independent reviewer (radiological and clinical). Par. who initiated alternative anti-cancer therapy prior to disease recurrence or death were treated as censored at the last assessment prior to the time of this initiation. For par. whose disease did not recur or who did not die, DFS was censored at the time of the last independently assessed radiological scan (where initiation of alternative anti-cancer therapy had not commenced). Par. who missed >=2 consecutive disease assessments were censored at the last assessment prior to the missed assessments. Par. considered to have malignant disease at Baseline were censored at the time of randomization. 99999 represents NA - insufficient number of events to calculate value.

Primary

From randomization until the earliest date of disease recurrence or death due to any cause (average of 101 study weeks)

Placebo v Lapatinib 1500 mg

688

Pre-specified

Placebo v Lapatinib 1500 mg

688

Pre-specified

1.1

2-sided

OS is defined as the time from randomization until death due to any cause. For participants who did not die, the time to death was censored at the time of last visit/contact. 99999 represents NA - insufficient number of events to calculate value.

Secondary

From randomization until death due to any cause (average of 131 study weeks)

DSS is defined as the time from randomization until death due to head and neck cancer. Participants whose death was not related to the disease under study were treated as competing risks at the time death occured. Participants who were alive were censored at the time of their last visit. 99999 represents NA - insufficient number of events to calculate value.

Secondary

From randomization until death due to head and neck cancer (average of 131 study weeks)

TTLR is defined as the time from randomization until the first occurrence that local and/or regional recurrence is documented or the date of censor. Local relapse is defined as recurrent cancer in the primary tumor bed not clearly attributable to a second primary neoplasm. Regional relapse is defined as recurrent cancer in the neck not clearly attributable to a second primary neoplasm. All other events prior to locoregional recurrence were treated as competing risks at the time they occured. All other participants were treated as censored at the time of their last disease assessment. Participants with malignant disease at Baseline according to the independent review were censored at the time of randomization for the analysis of independently reviewed data. 99999 represents NA - insufficient number of events to calculate value.

Secondary

From randomization until thefirst occurrence that local and/or regional recurrence is documented or the date of censor (average of 101 study weeks)

TTDR is defined as the time from randomization until the first occurrence that distant relapse is documented. Distant relapse is defined as clear evidence of distant metastases (lung, bone, brain, etc.). Metastasis is defined as the spread of a cancer from one organ or part to another non-adjacent organ or part. All other events prior to a distant relapse were treated as competing risks at the time they occured. All other participants were treated as censored at the time of their last disease assessment. Participants with malignant disease at Baseline according to the independent review were censored at the time of randomization for the analysis of independently reviewed data. 99999 represents NA - insufficient number of events to calculate value.

Secondary

From randomization until the first documented occurrence that distant relapse is documented (average of 101 study weeks)

Participants who developed a second primary tumor at the time of the first recurrence or within 28 days of the first recurrence were measured. The criteria for a second primary tumor are as follows: a distinct lesion separated from the primary tumor site by >2 centimeters of normal epithelium; or a new cancer with different histology; or any cancer, regardless of site, occurring >=3 years after initial treatment. Participants with baseline disease were included in the denominator when calculating the percentage.

Secondary

From randomization until development of second primary tumor or within 28 days of first recurrence (average of 101 study weeks)

Extent of exposure is defined as the duration of treatment administered during the study. The mean duration of treatment is calculated as the number of days between the start of treatment and the end of treatment inclusive (i.e., treatment stop date minus treatment start date + 1). Participants were counted in a treatment phase (monotherapy, chemoradiotherapy, and maintenance) if they had received any dose in that phase. Participants randomized to placebo who received >=1 dose of lapatinib in error were included in the lapatinib arm. Safety Population (SP): all par. who were randomized and took >=1 dose of study medication. Only par. available at the specified time points were analyzed (represented by n=X, X in the category titles). Different par. may have been analyzed for different parameters, so the overall number of par. analyzed reflects everyone in the SP.

Secondary

From randomization until end of 1year maintenance treatment (average of 63 study weeks)

An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General Adverse AE/SAE module for a complete list of non-serious AEs occurring at a frequency threshold of 5% and SAEs.

Secondary

From the first dose of lapatinib/placebo until 5 days after the last dose (average of 141 study weeks)

Data are summarized using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3 (NCI CTC version 3.0) toxicity grades. Data are reported as the number of par. who had a grade 3 (G3) or grade 4 (G4) toxicity for the indicated chemistry parameters, where G3 indicates a severe toxicity and G4 indicates a life-threatening toxicity. Clinical chemistry parameters included: albumin, alkaline phosphatase (AP), alanine amino transferase (ALT), aspartate amino transeferase (AST), total bilirubin (TB), calcium, carbon dioxide content/bicarbonate (CO2/HCO3), creatinine, glucose, potassium, and sodium. The worst-case on-therapy visit includes any scheduled or unscheduled post-Baseline visit. Only those par. available at the specified time points were analyzed (represented by n=X, X in the category titles). Different par. may have been analyzed for different parameters, so the overall number of par. analyzed reflects everyone in the Safety Population.

Secondary

From Baseline (within 8 weeks prior to randomization [Day 1]) until the end of the maintenance period/early withdrawal (up to Study Week 64)

Data are summarized using the NCI CTC version 3.0 toxicity grades. Data are reported as the number of participants who had a grade 3 (G3) or grade 4 (G4) toxicity for the indicated hematological parameters, where G3 indicates a severe toxicity and G4 indicates a life-threatening toxicity. The worst-case on-therapy visit includes any scheduled or unscheduled post-Baseline visit. Hematology parameter included: hemoglobin, total neutrophils (TN), platelet count (PC), and White Blood Cell (WBC) count. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Secondary

From Baseline (within 8 weeks prior torandomization [Day 1]) until the end of the maintenance period/early withdrawal (up to Study Week 64)

Late radiation morbidity event data are summarized as the number of participants with late radiation morbidity events per system organ class (SOC). Late radiation effects are defined as those that first occur 90 days or more after the initiation of radiation therapy.

Secondary

From 180 days after completion of radiation until the last follow-up/withdrawal visit (average of 64 study weeks)

Blood pressure measurement included systolic blood pressure (SBP) and diastolic blood pressure (DBP) at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Secondary

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)

Heart rate (HR) was measured at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Secondary

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)

Body temperature was measured at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Secondary

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)

Body weight was measured at Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, End of CRT, MW 8, MW 16, MW 24, MW 32, MW 40, MW 48, MW 56, and at the time of withdrawal from IP. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Secondary

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)

A 12-lead ECG was recorded at Baseline, at the end of the CRT, at Maintenance Week 56, at withdrawal from IP, and at anytime post-baseline. Data are presented as clinically significant (CS) or not clinically significant (NCS) abnormal findings. The study investigator determined if an abnormal ECG finding was CS or NCS.Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Safety Population.

Secondary

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)

The Eastern Cooperative Oncology Group (ECOG) performance status scales and grades/criteria are used by doctors and researchers to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the participant, and to determine appropriate treatment and prognosis. Grade 0, fully active, able to carry on all pre-disease performance without restriction. Grade 1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Grade 2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about more than 50% of waking hours. Grade 3, capable of only limited selfcare; confined to bed or chair more than 50% of waking hours. Grade 4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. Grade 5, dead.

Secondary

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)

Change from Baseline (BL) in quality of life status was assessed using the FACT-H&N questionnaire, which is designed to measure multidimensional quality of life in participants with head and neck cancer. Change from Baseline was analyzed using parametric analysis of covariance (with the Baseline value as a covariate). The FACT-H&N questionnaire contains 39 items (27 general questions and 12 head and neck cancer-specific items) covering 4 dimensions and 1 subscale: physical well-being, social/family well-being, emotional well-being, functional well-being, and a head and neck cancer subscale. Possible subscale scores range from 0 to 36. Higher scores represent better quality of life. Data were adjusted for participant-reported quality of life scores at Baseline.

Secondary

From randomization until the last follow-up/withdrawal visit (up to 62 study weeks)

Change from Baseline in quality of life status was assessed using the EQ-5D scale, a 5-item health status measure and a visual analog rating scale. Change from Baseline was analyzed using parametric analysis of covariance (with the Baseline value as a covariate). The EQ-5D is a generic measure of self-reported health outcomes that is applicable to a wide range of health conditions and treatments. The EQ-5D covers health status in 5 domains (3 questions each): mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Each item is scored as follows: 1, no problems; 2, some moderate problems; 3, extreme problems. The possible EQ-5D index utility values range from 0.594 to 1, and the thermometer score ranges from 0 to 100. Higher scores represent better quality of life. Data were adjusted for participant-reported quality of life scores at Baseline.

Secondary

From randomization until the last follow-up/withdrawal visit (up to 62 study weeks)

Biomarkers (which influence clinical response) assessed from tumor tissues included P16, Human Papilloma virus (HPV), and Epidermal Growth Factor Receptor (EGFR)/Epidermal Growth Factor Receptor 1 (ErbB1). Biomarker expression is presented as positive, negative, or unknown. Participants in the ErbB1-positive category include those with results of positive or strongly positive.

Secondary

Baseline (BL; within 8 weeks prior to randomization [Day 1]) (up to Study Week 1)

LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart with each contraction. LVEF was assessed using echocardiogram (ECHO: a test of the action of the heart using ultrasound waves to produce a visual display, for the diagnosis or monitoring of heart disease ) and multigated acqusition scans (MUGA scan: a noninvasive diagnostic test used to evaluate the pumping function of the ventricles). Data from the ECHO and MUGA scans were combined, and the absolute change from Baseline (Abs) data are presented according to the following categories: No change or any increase, 0-<10% decrease, 10-19% decrease, >=20% decrease, >=10% decrease and >=the Lower Limit of Normal (LLN), >=10% decrease and below LLN, >=20% decrease and >=LLN, or >=20% decrease and below LLN. The relative percent change from Baseline (Rel) data are presented according to the following categories: >=20% decrease and >=LLN and >=20% decrease and below LLN.

Secondary

From the end of the CRT until the last follow-up visit (up to 141 study weeks)

Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of study medication until the follow up of treatment (average of 141 study weeks).

SAEs and non-serious AEs were reported for members of the Safety Population, comprised of all participants who were randomized and took at least one dose of study medication. Participants randomized to placebo who received >=1 dose of lapatinib in error were included in the lapatinib arm.

3.0

Placebo

Lapatinib 1500 mg