Lapatinib Versus Placebo Given Concurrently With Cisplatin And Radiotherapy In Patients With Unresected Head And Neck Cancer

Study Overview
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Brief Summary
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This is a phase II study comparing the effects of lapatinib versus placebo when administered concurrently with cisplatin and radiotherapy followed by 1 year monotherapy with lapatinib or placebo. The study is designed to evaluate and compare the two treatment groups with respect to complete response rate at 6 months following chemoradiation completion.

Official Title
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A Randomized, Double-blind, Placebo Controlled, Multicentre, Phase II Study of Oral Lapatinib in Combination With Concurrent Radiotherapy and Cisplatin Versus Radiotherapy and Cisplatin Alone, in Subjects With Stage III, IVA, B Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Conditions
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Neoplasms, Head and Neck

Intervention / Treatment
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* Drug: Lapatinib oral tablets
* Drug: radiotherapy
* Drug: cisplatin chemotherapy


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 or more of the following sites: oral cavity, oropharynx, hypopharynx and larynx; Multiple primary tumours will: Have to be histologically proven; Have to be anatomically distant and surrounded by normal tissue; Exclude distant metastasis. Prior to enrolment subjects must have ErbB1 over-expression determined by immunohistochemistry (IHC) 3+ as assessed by a central laboratory; Subjects with stage III and IVA/IVB disease, who are to receive cisplatin chemotherapy and radiation therapy as primary treatment (total dose 65 - 70 Gy); Subjects with any Tis, T1 or T2 disease regardless of N stage, are excluded. Subjects with distant metastases, ie Stage IVC, are excluded. Willing and able to have a tumour biopsy taken at screening; For patients who have had prior tumour biopsy, an adequate archived specimen must be available. Male or female ≥18 years of age; Criteria for female subjects or female partners of male subjects: Non-child-bearing potential (i.e., women with functioning ovaries who have a GM2005/00448/00 CONFIDENTIAL EGF105884 22 current documented tubal ligation or hysterectomy, or women who are postmenopausal); Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhoea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following: Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or Consistent and correct use of one of the following acceptable methods of birth control: male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; implants of levonorgestrel; injectable progestogen; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only); or barrier methods, including diaphragm or condom with a spermicide. ECOG performance status 0, 1 or 2; Subjects must have adequate haematological, renal and hepatic function; Calculated creatinine clearance ≥50 ml/min as determined by the modified method of Cockcroft and Gault or by the EDTA method. Absolute neutrophil count ≥1,500/μl, platelets ≥100,000/μl. Haemoglobin ≥9gm/dL (5mmol/L). Aspartate (AST) and alanine transaminase (ALT) less than 4 times the upper limit of the normal range (ULN). Total bilirubin ≤2.0 mg/dL. Left ventricular ejection fraction (LVEF) within the institutional normal ranges as measured by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan; Able to swallow tablets whole or swallow a suspension of tablets dissolved in water at study inclusion; The use and timing of feeding tube is optional. If necessary, the suspension may be administered via percutaneous endoscopic gastrostomy (PEG), percutaneous jejunostomy tube (J- Tube), or a nasogastric tube (NG or Dobhoff type tube). Life expectancy of at least 6 months in the best judgment of the investigator. Exclusion criteria: Nasopharyngeal, paranasal sinuses or nasal cavity tumours; Any prior or current treatment for invasive head and neck cancer of any kind. This will include but is not limited to: prior tyrosine kinase inhibitors, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent; Concurrent use of CYP3A4 inducers or inhibitors. A standard 3-day course of dexamethasone for the prevention of cisplatin-induced nausea and vomiting is permitted; Subjects with known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure; History of another malignancy within the last 5 years, with the exception of completely resected basal or squamous cell skin cancer, or successfully treated in-situ carcinoma. History of non-invasive lesion or in-situ carcinoma, including in the head and neck region that was successfully treated with surgery, photodynamics or laser, will be permitted; Peripheral neuropathy ≥ grade 2; Pregnant or lactating females (female subjects of child-bearing potential will undertake pregnancy testing at screening and during study completion/withdrawal visits); Malabsorption syndrome, disease significantly affecting GI function, that could affect absorption of lapatinib; History of allergic reactions to appropriate antiemetics (e.g. 5-HT3 antagonists) to be administered with platinum chemotherapy; The investigator considers the subject unfit for the study as a result of the medical interview, physical examinations, or screening investigations;

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib<br>1500mg lapatinib orally daily | Drug: Lapatinib oral tablets<br>* Lapatinib is administered orally once daily.<br>Drug: radiotherapy<br>* Radiotherapy is given either as conventional fractionation using Two-dimensional (2D) or conformal techniques, or as Intensity Modulated Radiation Therapy (IMRT). Radiation therapy will be standardised throughout the study. Radiation therapy is given only once daily, with a dose/fraction not exceeding 2.5Gy, to a total dose of 65 Gy (IMRT) or 70 Gy (2D or 3D RT) to the gross site of disease .<br>Drug: cisplatin chemotherapy<br>* Cisplatin is administered intravenously at a dose of 100mg/m2 on days 1, 22 and 43 of radiotherapy (approximately Study Days 8, 29 and 50).<br>* Other names: Lapatinib oral tablets;|
| Placebo Comparator: Placebo<br>orally daily | Drug: Lapatinib oral tablets<br>* Lapatinib is administered orally once daily.<br>Drug: radiotherapy<br>* Radiotherapy is given either as conventional fractionation using Two-dimensional (2D) or conformal techniques, or as Intensity Modulated Radiation Therapy (IMRT). Radiation therapy will be standardised throughout the study. Radiation therapy is given only once daily, with a dose/fraction not exceeding 2.5Gy, to a total dose of 65 Gy (IMRT) or 70 Gy (2D or 3D RT) to the gross site of disease .<br>Drug: cisplatin chemotherapy<br>* Cisplatin is administered intravenously at a dose of 100mg/m2 on days 1, 22 and 43 of radiotherapy (approximately Study Days 8, 29 and 50).<br>* Other names: Lapatinib oral tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants (Par.) With Complete Response (CR), as Assessed by Independent Radiological Review | Participants with CR are defined as those who achieved a complete tumor response at 6 months after the completion of the chemoradiation treatment (CRT), as assessed by independent radiological review. Tumor response was assessed using modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Per RECIST, CR is defined as the disappearance of all target and non-target lesions. Data are based on Week 24 scans from participants receiving study treatment at that time and on those in follow-up. | From the date of randomization until 6 months post chemoradiation treatment, assessed for a median time of 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With CR, as Assessed by the Investigator | Participants with CR are defined as those who achieved a complete tumor response at 6 months after the completion of the CRT, as determined by the investigator. Tumor response was assessed using modified RECIST criteria. Per RECIST, CR is defined as the disappearance of all target and non-target lesions. Data are based on Week 24 scans from participants receiving study treatment at that time and on those in follow-up. | From the date of randomization until 6 months post chemoradiation treatment, assessed after a median time of 13 months of follow-up | 
| Progression-Free Survival (PFS), as Assessed by the Investigator | PFS=the time from randomization until the earliest date of disease progression or death due to any cause, if sooner. Per RECIST, progressive disease=a >=20% increase in the sum of the longest diameter of target lesions (TLs), or the appearance of >=1 new L, symptomatic progression and/or unequivocal progression of existing non-TLs. For participants who did not progress or die at the time of reporting (data cut-off 1-Aug-2014), PFS data were censored at the time of the last investigator assessed radiological scan preceding the initiation of any alternative anti-cancer therapy. | From the date of randomization until the date of disease progression or death due to any cause, assessed after a median of 22 months of follow-up | 
| Overall Survival (OS) | OS is defined as the time from randomization until death due to any cause. Time to death (data cut-off 1-Aug-2014) was censored at the time of last contact for participants who did not die. | From the date of randomization until the date of death due to any cause, assessed after a median of 30.9 months | 
| Number of Participants Who Died Due to Progressive Disease | The number of participants who died due to progressive disease (a >=20% increase in the sum of the longest diameter of target lesions, or the appearance of >=1 new lesion, symptomatic progression and/or unequivocal progression of existing non-target lesions), or died due to head and neck cancer without evidence of disease progression, after randomization in the study is presented, using a data cut of 1 August 2014. | From the date of randomization until the date of death due to disease under study, assessed after a median of 30.9 months | 
| Disease-specific Survival | Disease-specific survival is defined as the time from randomization until death due to head and neck cancer. | From the date of randomization until the date of death due to disease, assessed after a median of 13 months of follow-up | 
| Number of Participants With Loco-regional Recurrence of Initial Disease | Participants with loco-regional recurrence were those who had progression of disease in the T and N sites. Per the Tumor, Node, and Metastases (TNM) staging of tumors: T describes the size of the tumor and whether it has invaded nearby tissue, and N describes regional lymph nodes that are involved. If a participant had progression in the T or N sites, then the participant was counted as having had an event of interest. | From the date of randomization until progression in the T or N site or death due to any cause, assessed after a median of 30.9 months | 
| Loco-regional Control | Loco-regional control is defined as the time from the date of randomization until progression in the T or N site. Participants who died or had secondary primary malignancies in the head and neck region outside of the T and N site or distant metastasis were not counted as an event and were instead treated as competing risks. Per the TNM staging of tumors: T describes the size of the tumor and whether it has invaded nearby tissue, and N describes regional lymph nodes that are involved. Due to the minimal events reported (data cut-off 30-Sep-2010), valid analysis could not be performed for loco-regional control rate. | From the date of randomization until progression in the T or N site or death due to any cause, assessed after a median of 30.9 months | 
| Number of Participants With Distant Recurrence of Initial Disease | Participants were analyzed for the occurrence of distant metastasis (spread of a disease from one organ or part to another non-adjacent organ or part) after randomization in the study until data cut-off date 1-Aug-2014. Participants who died or had recurrence of disease in the T or N sites or secondary primary malignancies in the head and neck region outside of the original T and N site were not counted as an event and were instead treated as competing risks. | From the date of randomization until the first occurrence of distant metastasis, assessed after a median of 30.9 months | 
| Distant Relapse | Distant relapse is defined as the time from the date of randomization until the first occurrence of distant metastasis (spread of a disease from one organ or part to another non-adjacent organ of part). Participants who died or had recurrence of disease in the T or N sites or secondary primary malignancies in the head and neck region outside of the original T and N site were not counted as an event and were instead treated as competing risks. | From the date of randomization until the first occurrence of distant metastasis, assessed after a median of 30.9 months | 
| Number of Participants With Overall Response (OR), as Assessed by the Investigator | Participants with OR were those who achieved either a CR or partial response (PR) from the assessment of overall tumor response at 6 months (24 weeks) following completion of CRT (data cut-off 30-Sep-2010). Per RECIST, CR is defined as the disappearance of all target and non-target lesions; PR is defined as at least a 30% decrease in the sum of the long diameter (LD) of target lesions, taking as a reference, the baseline sum LD. Data are based on Week 24 scans from participants receiving study treatment at that time point. | From the date of randomization until 6 months post chemoradiation treatment, assessed for a median of 13 months | 
| Number of Participants Positive and Negative for the Expression of Biomarkers in Tumor Tissue: Human Epidermal Growth Factor Receptor (HER)-1, HER2, HER3, HER4, P16, and Transforming Growth Factor (TGF-alpha) | Paraffin-embedded tissue block (or sections) from archived tumor tissue sample, if available (from time of original diagnosis) or fresh tumor tissue, was sent for testing to determine intra-tumoral biomarker expression by immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) assay. Stained tumor slides or tissue micro arrays (TMAs) were scored by a pathologist from 0 (no expression) to 3+ (high expression). An expression level of >=2+ was considered positive. | Up to 28 days prior to the date of the first dose of lapatinib/placebo start | 
| Plasma Proteome Analysis | Proteomic analyses of blood plasma samples were to be conducted to identify any changes in the proteome profile that could be related to the treatment response. Examination of pre-dosing (screening) plasma protein profiles could uncover novel blood-borne protein candidate biomarkers/profiles, which could be used to predict drug response. | From up to 28 days prior to the first dose of lapatinib/placebo start to 8 weeks after the first dose | 
| Analysis of Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) From Tumor Samples | No analysis was performed for tumor sample RNA/DNA. | Screening | 
| Number of Participants Negative and Positive for Human Papilloma Virus (HPV) Infection, as Determined From Tumor Samples | Analysis was performed for HPV infection analysis from the tumor biopsy samples obtained during the Screening period. p16 was used as a marker for HPV; thus, negative participants did not have the p16 marker. | Up to 28 days prior to the first dose of lapatinib/placebo | 
| Number of Participants Positive and Negative for Biomarker HER1/ErbB1 Categorized in the Indicated Independent Review Panel-assessed Tumor Responses by Expression of Biomarkers From Tumor Tissue: Sensitivity Analysis - 0 Versus (1, 2, 3) | Tumor tissue (fresh or archived) was sent to a central laboratory for biomarker HER1/ErbB1 and tumor genetics analysis up to 1 week after randomization. Per RECIST: CR, disappearance of all lesions; PR, a >=30% decrease in the sum of the longest dimensions (LD) of the target lesions (TLs) taking as a reference the baseline sum LD; Progressive disease (PD), a >=20% increase in the sum of the LD of TLs, or the appearance of >=1 new lesion; Stable Disease (SD), neither PR nor PD, persistence of >=1 non-TL. 0=negative; 1, 2, 3=positive (increasing level of biomarker expression). | From the date of randomization until 6 months post chemoradiation treatment, assessed for up to 24 weeks | 
| Number of Participants Positive and Negative for Biomarker HER1/ErbB1 Categorized in the Indicated Independent Review Panel-assessed Tumor Responses by Expression of Biomarkers From Tumor Tissues: Sensitivity Analysis - 0, 1, 2 Versus 3 | Tumor tissue (fresh or archived) was sent to a central laboratory for biomarker HER1/ErbB1 and tumor genetics analysis up to 1 week after randomization. Per RECIST: CR, disappearance of all lesions; PR, a >=30% decrease in the sum of the longest dimensions (LD) of the target lesions (TLs) taking as a reference the baseline sum LD; Progressive disease (PD), a >=20% increase in the sum of the LD of TLs, or the appearance of >=1 new lesion; Stable Disease (SD), neither PR nor PD, persistence of >=1 non-TL. 0=negative; 1, 2, 3=positive (increasing level of biomarker expression). | From the date of randomization until 6 months post chemoradiation treatment, assessed for up to 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neck Cancer, Locally advanced head and neck cancer, locally advanced, Head and Neck cancer, lapatinib, EGFR/ErbB2 inhibitor, Head Cancer