Study Of Adjuvant Lapatinib In High-Risk Head And Neck Cancer Subjects After Surgery

Study Overview
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Brief Summary
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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
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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)

Official Title
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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)

Conditions
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Neoplasms, Head and Neck

Intervention / Treatment
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* Drug: Lapatinib
* Radiation: Chemoradiation
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib+Chemoradiation<br>Adjuvant concurrent chemoradiotherapy plus lapatinib 1500 mg once daily for 6 to 7 weeks, followed by lapatinib 1500 mg once daily for one year. Chemoradiotherapy=total dose of 66Gy over 6-7 weeks plus cisplatin 100mg/m2 on days 1,2 and 43 of the course of radiotherapy. Lapatinib is also given at 1500 mg once daily for 3-7 days prior to the start of chemoradiotherapy. | Drug: Lapatinib<br>* Dual ErbB1/2 inhibitor<br>|
| Placebo Comparator: Placebo+Chemoradiation<br>Adjuvant concurrent chemoradiotherapy plus placebo once daily for 6 to 7 weeks, followed by placebo once daily for one year. Chemoradiotherapy = total dose of 66Gy over 6-7 weeks plus cisplatin 100mg/m2 on days 1,2 and 43 of the course of treatment. Placebo is also given once daily for 3-7 days prior to the start of chemoradiotherapy. | Radiation: Chemoradiation<br>* Radiation plus platinum based chemotherapy<br>Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) | 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). Participants 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 participants 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). Participants who missed two or more consecutive disease assessments were censored at the last assessment prior to the missed assessments. Participants considered to have malignant disease at Baseline were censored at the time of randomization. | From randomization until the earliest date of disease recurrence or death due to any cause (average of 101 study weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | From randomization until death due to any cause (average of 131 study weeks) | 
| Disease Specific Survival (DSS) | 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. | From randomization until death due to head and neck cancer (average of 131 study weeks) | 
| Time to Locoregional Recurrence (TTLR) | 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. | From randomization until thefirst occurrence that local and/or regional recurrence is documented or the date of censor (average of 101 study weeks) | 
| Time to Distant Relapse (TTDR) | 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. | From randomization until the first documented occurrence that distant relapse is documented (average of 101 study weeks) | 
| Number of Participants With a Second Primary Tumor | 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. | From randomization until development of second primary tumor or within 28 days of first recurrence (average of 101 study weeks) | 
| Extent of Exposure | 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. | From randomization until end of 1year maintenance treatment (average of 63 study weeks) | 
| Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) | 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. | From the first dose of lapatinib/placebo until 5 days after the last dose (average of 141 study weeks) | 
| Number of Participants With the Indicated Chemistry Toxicities by Maximum Toxicity Grade (G3 and G4) at the Worst-case On-therapy Visit | 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 participants 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. | From Baseline (within 8 weeks prior to randomization [Day 1]) until the end of the maintenance period/early withdrawal (up to Study Week 64) | 
| Number of Participants With the Indicated Hematological Toxicities by Maximum Toxicity Grade (G3 and G4) at the Worst-case On-therapy Visit | 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. | From Baseline (within 8 weeks prior torandomization [Day 1]) until the end of the maintenance period/early withdrawal (up to Study Week 64) | 
| Number of Participants With On-therapy and Follow-up Late Radiation Morbidity Events | 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. | From 180 days after completion of radiation until the last follow-up/withdrawal visit (average of 64 study weeks) | 
| Change From Baseline in Blood Pressure at the Indicated Time Points | 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. | 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) | 
| Change From Baseline in Heart Rate at the Indicated Time Points | 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. | 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) | 
| Change From Baseline in Body Temperature at the Indicated Time Points | 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. | 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) | 
| Change From Baseline in Body Weight at the Indicated Time Points | 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. | 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) | 
| Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) Findings at the Indicated Time Points | 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. | 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) | 
| Number of Participants With the Indicated Eastern Cooperative Oncology Group (ECOG) Performance Status Value | 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. | 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 in Quality of Life Status as Assessed by the Functional Assessement of Cancer Therapy-Head and Neck (FACT-H&N) Questionnaire | Change from Baseline 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. | From randomization until the last follow-up/withdrawal visit (up to 62 study weeks) | 
| Change From Baseline in Quality of Life Status as Assessed by the EuroQol-5D (EQ-5D) Scale | 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. | From randomization until the last follow-up/withdrawal visit (up to 62 study weeks) | 
| Number of Participants With the Indicated Biomarker Expression Status | 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. | Baseline (BL; within 8 weeks prior to randomization [Day 1]) (up to Study Week 1) | 
| Number of Participants With the Indicated Worst-case On-therapy Left Ventricular Ejection Fraction (LVEF) Change From Baseline | 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. | From the end of the CRT until the last follow-up visit (average of 141 study weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer of the Head and Neck, Neck cancer, Adjuvant, Head and neck cancer, High-risk head and neck cancer, Post-surgery, Head cancer