A Study Of Lapatinib Versus Placebo Followed By Chemoradiation In Patients With Locally Advanced Head And Neck Cancer

Study Overview
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Brief Summary
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This is a study comparing the activity of lapatinib versus placebo followed by chemoradiation. This study is designed to explore the effects of lapatinib monotherapy on apoptosis/necrosis, in pre-treatment and post-treatment tumour tissue samples in subjects with locally advanced squamous cell carcinoma of head and neck.

Official Title
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A Randomized, Single Blinded, Placebo-controlled, Multi-centre, Phase II Study of Lapatinib in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Conditions
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Squamous Cell Carcinoma of Head and Neck

Intervention / Treatment
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* Drug: Lapatinib oral tablets
* Drug: 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 or cytologically confirmed diagnosis of SCCHN. Stage III, IVA and IVB disease will be eligible, who are to receive chemoradiation therapy as primary treatment (total dose ≥ 65 Gy). Subjects with distant metastases (stage IVC) will be excluded. Willing and able to have a tumour biopsy taken at screening and a second tumour biopsy taken during lapatinib/placebo administration. 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 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. Eastern Cooperative Oncology Group (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 method of Cockcroft and Gault [Cockcroft, 1976] 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 three 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) scans. Able to swallow tablet whole or swallow a suspension of the tablet dissolved in water at study inclusion. If necessary, the suspension may be administered via percutaneous endoscopic gastrostomy (PEG), percutaneous jejunostomy tube (JTube), or a nasogastric tube (NG or Dobhoff type tube). Life expectancy of at least 6 months as judged by the investigator. Exclusion criteria: Subjects with paranasal sinuses, nasopharyngeal and nasal cavity tumours; Subjects who have received prior systemic chemotherapy given with curative intent; Subjects who received prior radiotherapy; Prior or concurrent treatment with tyrosine kinase inhibitors; Use of any investigational agent within 30 days or 5 half-lives, whichever is longer, preceding the first dose of lapatinib; Concurrent use of CYP3A4 inducers or inhibitors; 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 of head and neck that was successfully treated with surgery, photodynamics or laser, will be permitted; Distant metastases, ie Stage IVC; Females or males of child-bearing potential who are sexually active, if they do not agree to practice an effective method of contraception. (For example oral contraceptives, IUD or diaphragm plus spermicide); Pregnant or lactating females (female patients of childbearing 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 diuretics or antiemetics (e.g. 5-HT3 antagonists) to be administered with platinum-based chemotherapy; The investigator considers the patient unfit for the study as a result of the medical interview, physical examinations, or screening investigations; Subjects taking any prohibited medication (See Section 8.2) Other Eligibility Criteria Considerations: To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings,precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: investigator's brochure IB and any IB supplements, and expedited investigator safety reports

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib<br> | Drug: Lapatinib oral tablets<br> <br> * Other names: radiotherapy;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of the Apoptotic Index During Treatment Phase | Apoptotic Index-TUNEL Assay is a method which counts a total of at least 1000 neoplastic nuclei(Cells with morphological changes defining cell death) subdivided in 10 fields chosen randomly at 400x magnification. A 'responder' was defined as having 20% cell death. | Baseline and Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Cell Proliferation Rate of the Ki-67 Proliferative Index in Tumour Biopsy Samples During Treatment Phase | The Ki-67 protein is expressed in all phases of the cell cycle except G0 (low level phase) and serves as a good marker for cell proliferation. Scoring is assessed by point counting 500 to 1000 cells, and is reported as percent positive cells. 20% positive cells to define positive (i.e. high risk) | Baseline and Week 2 | 
| Overall Radiological Response After Treatment Phase in mITT Population | Over all: Complete Response (CR)- absence of lesions. Partial Response (PR)- CR or PR of target lesions and incomplete response (IC) or stable disease (SD) in other lesions with no new lesions or progressive disease (PD). Stable Disease (SD)-no PD or Response. Progressive Disease (PD)-PD or new lesions. Not Evaluable(NE)- no other definitions. Number of subjects included those who had a scan immediately post lapatanib/placebo monotherapy. | Baseline and End of Treatment (Week 2 - 6) | 
| Overall Radiological Response After Follow-up Phase in mITT Population | Over all: Complete Response(CR)-absence of lesions. Partial Response(PR)- CR or PR of target lesions and incomplete response (IC) or stable disease (SD)in other lesions with no new lesions or progressive disease (PD). Stable Disease(SD)-no PD or Response. Progressive Disease(PD)-PD or new lesions. Not Evaluable(NE)- no other definitions. Number of subjects included those who were considered evaluable if they completed a full course of chemoradiotherapy and were able to provide a baseline and follow-up scan following the completion of chemoradiation. | Baseline and End of Follow-up (Week 19 - 25) | 
| Overall Radiological Response After Treatment Phase in ITT Population | Over all: Complete Response (CR)-absence of lesions. Partial Response (PR)- CR or PR of target lesions and incomplete response (IC) or stable disease (SD) in other lesions with no new lesions or progressive disease (PD). Stable Disease (SD)-no PD or Response. Progressive Disease (PD)-PD or new lesions. Not Evaluable(NE)- no other definitions. | Baseline and End of Treatment (Week 2 - 6) | 
| Overall Radiological Response After Follow-up Phase in ITT Population | Over all: Complete Response (CR) - absence of lesions. Partial Response (PR) - CR or PR of target lesions and incomplete response (IC) or stable disease (SD) in other lesions with no new lesions or progressive disease (PD). Stable Disease (SD)- no PD or Response. Progressive Disease (PD)- PD or new lesions. Not Evaluable(NE)- no other definitions. | Baseline and End of Follow-up (week 19 - 25) | 
| Number of Circulating Tumor Cells at Baseline in mITT Population | This measures the participants with Circulating Tumor Cells (CTC's)Pre-Treatment numbers of 0 to >= 4. CTC's are tumor cells that escape from the primary tumor into the bloodstream and travel through the circulation to distant sites where they develop into secondary tumors. | Baseline | 
| Number of Participants With Circulating Tumor Cells After Treatment Phase in mITT Population | This measures the participants with Circulating Tumor Cells (CTC's) after treatment numbers of 0 to >= 4. CTC's are tumor cells that escape from the primary tumor into the bloodstream and travel through the circulation to distant sites where they develop into secondary tumors. | End of Treatment (week 2 - 6) | 
| Number of Participants With Circulating Tumor Cells After Chemoradiotherapy Phase in mITT Population | This measures the participants with Circulating Tumor Cells (CTC's) after chemoradiotherapy numbers of 0 to >= 4. CTC's are tumor cells that escape from the primary tumor into the bloodstream and travel through the circulation to distant sites where they develop into secondary tumors. | End of Chemoradiotherapy (week 10 - 13) | 
| Number of Biomarkers Including ErbB1, ErbB2, pErbB1, and pErb2 at Baseline and During Treatment Phase | Estrogen Receptor (ER) variants, ERB-B2 and ERB B-5 consist of the major proportion of ER expression both in normal and cancer tissues. The exact role of these markers are unknown. Acronyms defined: ICH (immunohistochemical) and FISH (fluorescence in situ hybridization). | Baseline and Week 2 | 
| Number of Biomarkers Including Tumor Protein 53 and HPV During Treatment Phase | Tumor Suppressor p53 is welcomed and described as the guardian angel gene, it conserves stability by preventing genome mutation. Human Papillomavirus (HPV) biomarker is un-welcomed and is found to be an important precursor cancers of the head and neck. HPV biomarkers have the ability to bind to and inactivate the Tumor Suppressor p53 biomarker. | Week 2 | 
| Summary of Adverse Events by Maximum Toxicity Grade Started During Treatment Phase | Toxicity Grading scale 0=none, 1=transient symptom, 2=mild symptom that does not interfere with activities of daily living (ADL's) 3=mild but interfers with ADL's w/o hospitalization. 4=requires hopitalization 5=Death. | Week 1 through Week 6 | 
| Summary of Adverse Events by Maximum Toxicity Grade (Grade 3 or Higher) Started During or After the Chemoradiotherapy Phase | Toxicity Grading scale 0=none, 1= transient symptom, 2=mild symptom that does not interfere with activities of daily living (ADL's) 3=mild but interfers with ADL's w/o hospitalization. 4=requires hopitalization 5=Death. | Week 10 through 25 | 
| Comparison of Overall Response During Treatment Phase Using CT/MRI and PET Information | Position Emission Tomography (PET) scans 3-D images are read alongside CT or magnetic resonance imaging (MRI) scans, the combination gives both anatomic and metabolic information. CT = Computerized axial tomography; a type of x-ray for dense areas of the body. MRI = Magnetic Resonance Imaging which captures a picture using Magnets. Better = improvement in response, Worse = response was downgraded. | Week 2 - 4 | 
| Comparison of Overall Response During Follow up Phase Using CT/MRI and PET Information | Position Emission Tomography (PET) scans 3-D images are read alongside CT or magnetic resonance imaging (MRI) scans, the combination gives both anatomic and metabolic information. CT = Computerized axial tomography; a type of x-ray for dense areas of the body. MRI = Magnetic Resonance Imaging which captures a picture using Magnets. Better = improvement in response, Worse = response was downgraded. | weeks 19 - 25 | 
| Summary of Adverse Events Experienced by 15% or More Subjects in Either Treatment Group | Definition of an adverse event is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Week 1 through 25 | 
| Summary of Fatal/Serious Adverse Events During or After Chemoradiotherapy Phase | Events which started during or After the Chemoradiotherapy Phase. Definition of a serious adverse event is any untoward medicinal occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other. | Week 10 through 25 | 
| Summary of Serious Adverse Events During or After Chemoradiotherapy Phase | Events which started during or After Chemoradiotherapy Phase. Definition of a serious adverse event is any untoward medicinal occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other. | Week 10 through 25 | 
| Adverse Events by Maximum Toxicity Grade 3 During or After Chemoradiotherapy Phase | Events which started during or after Chemoradiotherapy Phase. Grade 3 are severe and undesirable Adverse Event (significant symptoms requiring hospitalization or invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation). | Week 10 through 25 | 
| Adverse Events (AEs) by Maximum Toxicity Grade 4 During or After Chemoradiotherapy Phase | Events which started during or after Chemoradiotherapy Phase. Grade 4 are life-threatening or disabling Adverse Event (complicated by acute, life-threatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, sepsis. Life-threatening physiologic consequences; need for intensive care or emergent invasive procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation). | Week 10 through 25 | 
| Adverse Events by Maximum Toxicity Grade 5 During or After Chemoradiotherapy Phase | Events which started during or after Chemoradiotherapy Phase. Grade 5 are death related to Adverse Event. | Week 10 through 25 | 
| Relative Change From Baseline of Ktrans Median (1/Min) After 2 - 4 Weeks of Treatment | Dynamic Contrast enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an administered contrast agent from -intra into the extravascular tissue over time. Ktrans estimates blood flow and relates to the ease of exchange into extravascular spaces. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g.,tissue perfusion, vessel permeability, vascular surface area, and extracellular/vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Kep Mean (1/Min) After 2 - 4 Weeks of Treatment | DCE-MRI tracks the diffusion of an intravascularly administered contrast agent into the extravascular tissue over time. Over a period of time, the contrast agent diffuses back into the vasculature (described by the rate constant or Kep). The lower the Kep, the longer the contrast remains in the extravascular space and is more prolonged. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g., vessel permeability, etc.) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Kep Perfused (1/Min) After 2 - 4 Weeks of Treatment | DCE-MRI tracks the diffusion of an intravascularly administered contrast agent into the extravascular tissue over time. Over a period of time, the contrast agent diffuses back into the vasculature (described by the rate constant or Kep). The lower the Kep, the longer the contrast remains in the extravascular space and is more prolonged. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g., vessel permeability, etc.) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Kep Whole (1/Min) After 2 - 4 Weeks of Treatment | DCE-MRI tracks the diffusion of an intravascularly administered contrast agent into the extravascular tissue over time. Over a period of time, the contrast agent diffuses back into the vasculature (described by the rate constant or Kep). The lower the Kep, the longer the contrast remains in the extravascular space and is more prolonged. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g., vessel permeability, etc.) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Ktrans Mean (1/Min) After 2 - 4 Weeks of Treatment | Dynamic Contrast enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an administered contrast agent from -intra into the extravascular tissue over time. Ktrans estimates blood flow and relates to the ease of exchange into extravascular spaces. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g.,tissue perfusion, vessel permeability, vascular surface area, and extracellular/vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Ktrans Perfused (1/Min) After 2 - 4 Weeks of Treatment | Dynamic Contrast enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an administered contrast agent from -intra into the extravascular tissue over time. Ktrans estimates blood flow and relates to the ease of exchange into extravascular spaces. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g.,tissue perfusion, vessel permeability, vascular surface area, and extracellular/vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Ktrans Whole (1/Min) After 2 - 4 Weeks of Treatment | Dynamic Contrast enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an administered contrast agent from -intra into the extravascular tissue over time. Ktrans estimates blood flow and relates to the ease of exchange into extravascular spaces. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g.,tissue perfusion, vessel permeability, vascular surface area, and extracellular/vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of IAUC Median (90) After 2 - 4 Weeks of Treatment | Dynamic Contrast - enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an intravascularly administered contrast agent from intravascular into the extravascular tissue over time. Initial area under the contrast (IAUC), tracks the concentration versus time curve 90 seconds after contrast injection (IAUC90). By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor microenvironment (e.g., tissue perfusion, vessel permeability, vascular surface area, and extracellular-extra vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of IAUC Mean (90) After 2 - 4 Weeks of Treatment | Dynamic Contrast - enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an intravascularly administered contrast agent from intravascular into the extravascular tissue over time. Initial area under the contrast (IAUC), tracks the concentration versus time curve 90 seconds after contrast injection (IAUC90). By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor microenvironment (e.g., tissue perfusion, vessel permeability, vascular surface area, and extracellular-extra vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Perfused IAUC (90) After 2 - 4 Weeks of Treatment | Dynamic Contrast - enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an intravascularly administered contrast agent from intravascular into the extravascular tissue over time. Initial area under the contrast (IAUC), tracks the concentration versus time curve 90 seconds after contrast injection (IAUC90). By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor microenvironment (e.g., tissue perfusion, vessel permeability, vascular surface area, and extracellular-extra vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Whole IAUC(90) After 2 - 4 Weeks of Treatment | Dynamic Contrast - enhanced Magnetic Resonance Imaging (DCE-MRI) tracks the diffusion of an intravascularly administered contrast agent from intravascular into the extravascular tissue over time. Initial area under the contrast (IAUC), tracks the concentration versus time curve 90 seconds after contrast injection (IAUC90). By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor microenvironment (e.g., tissue perfusion, vessel permeability, vascular surface area, and extracellular-extra vascular volume fraction) are determined. | Baseline, and Week 2 - 4 | 
| Relative Change From Baseline of Kep Median (1/Min) After 2 - 4 Weeks of Treatment | DCE-MRI tracks the diffusion of an intravascularly administered contrast agent into the extravascular tissue over time. Over a period of time, the contrast agent diffuses back into the vasculature (described by the rate constant or Kep). The lower the Kep, the longer the contrast remains in the extravascular space and is more prolonged. A volume transfer (i.e, 1/min) constant of contrast agent is used to determine vascular permeability. By plugging DCE-MRI results into an appropriate pharmacokinetic model, physiological parameters of the tumor (e.g., vessel permeability, etc.) are determined. | Baseline, and Week 2 - 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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squamous cell carcinoma of head and neck, lapatinib, ErbB1/ErbB2 inhibitor, apoptosis