Lapatinib and Radiation for Stage III-IV Head and Neck Cancer Patients Who Cannot Tolerate Concurrent Chemotherapy

Study Overview
=================
Brief Summary
-----------------
We propose to combine lapatinib with RT alone in patients with locally advanced head and neck cancer who cannot tolerate chemotherapy. The main objective of the study is to determine the efficacy of combining concurrent radiation and lapatinib in terms of time-to-progression (TTP) in this group of patients. In addition, we will determine the 2-year locoregional control rate (LRC), progression-free survival (PFS) and overall survival (OS) in these patients. We will also evaluate the profile and frequency of late toxicity, specifically mucosal and dermatologic toxicity, of the combination of lapatinib and RT in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Detailed Description
-----------------
There is substantial data to suggest that EGFR and Her-2/neu expressions are important predictors for prognosis in HNSCC. EGFR blockade with a monoclonal antibody in conjunction with radiotherapy has been shown to improve survival over radiotherapy alone in patients with locally advanced HNSCC. Dual inhibition of EGFR and ErbB2 tyrosine kinases results in greater inhibitory effect of the downstream signaling pathways in cancer cells than inhibition of either receptor alone. Phase I studies in HNSCC suggested that the drug is well tolerated when delivered either alone or concurrently with cisplatin based chemoradiotherapy in HNSCC. We propose to combine lapatinib with RT alone in patients with locally advanced HNSCC who cannot tolerate chemotherapy. The main objective of the study is to determine the efficacy of combining concurrent radiation and lapatinib in terms of time-to-progression (TTP) in this group of patients. In addition, we will determine the 2-year locoregional control rate (LRC), progression-free survival (PFS) and overall survival (OS) in these patients. We will also evaluate the profile and frequency of late toxicity, specifically mucosal and dermatologic toxicity, of the combination of lapatinib and RT in patients with locally advanced HNSCC.

Official Title
-----------------
A Multi-Institutional Phase II Study of Radiation and GW572016 (Lapatinib) for Patients With Stage III-IV Head and Neck Cancer Who Cannot Tolerate Concurrent Chemoradiotherapy.

Conditions
-----------------
Head and Neck Cancer, Carcinoma, Squamous Cell, Head and Neck Cancers

Intervention / Treatment
-----------------
* Drug: Lapatinib
* Procedure: Radiotherapy (radiation)
* Device: G.E. Healthcare 1.5T MR, systems revision 12.0 M5
* Device: DCE-MRI


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Newly diagnosed stage III-IV HNSCC, pathologically confirmed (HNSCC from unknown primary sites are allowed) No evidence of distant metastasis No prior radiation therapy to the head and neck sites. Able to sign a study-specific informed consent form. Women of childbearing potential and men with partners capable of producing offspring must be willing to practice acceptable methods of birth control to prevent pregnancy. Left ventricular ejection fraction (LVEF) within the institutional normal range as measured by ECHO (If ECHO cannot be performed or if the Investigator feels that it is not conclusive to evaluate LVEF, then a MUGA scan should be performed). Having one of the following parameters that would preclude the use of concurrent CRT: ECOG PS > 2. Creatinine > 1.3 or calculate or measure creatinine clearance < 60 ml/min. AST or ALT > 1.5 times normal limit but < 3 times normal limit Total bilirubin > 1.5 mg/dL but < 3mg/dL History of hearing loss that would preclude cisplatin chemotherapy. These would include the existing need of a hearing aid or a >= 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test. Pre-existing peripheral neuropathy that would preclude cisplatin chemotherapy Refuse or cannot tolerate chemotherapy Age 18 years or older Exclusion Criteria: Known hypersensitivity to lapatinib or any of the excipients of this product (quinazolines). Uncontrolled angina, arrhythmia or congestive heart failure at the time of HNSCC diagnosis and treatment. History of myocardial infarction < 6 months from study entry. Treatment with a non-approved or investigational drug within 30 days before Day 1 of study treatment. Prior treatment with EGFR or Her2/Neu directed therapies. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with Lapatinib. Absolute neutrophil count < 1500/uL

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radiotherapy and Lapatinib with DCE-MRI<br>DCE-MRI will precede radiotherpy before and after Lapatinib loading. 1500mg/d once daily oral Lapatinib will be administration for seven days prior to and throughout radiotherapy. Radiotherapy will be delivered as Intensity Modulated Radio Therapy (IMRT) using a G.E. Healthcare 1.5T MR, systems revision 12.0 M5 for a total dose of 70Gy delivered in 2-2.12 Gy/ fraction over the course of 6.5-7 weeks. | Drug: Lapatinib<br>* 1500 mg po daily orally<br>* Other names: GlaxoSmithKline;Procedure: Radiotherapy (radiation)<br>* Standard of Care<br>* Other names: IMRT - Intensity Modulated Radiotherapy;Device: G.E. Healthcare 1.5T MR, systems revision 12.0 M5<br>* Standard of Care, used to deliver IMRT<br>* Other names: G.E. Healthcare MRI Device and Software;Device: DCE-MRI<br>* A subset of patients received imaging before and after Lapatinib loading, prior to starting radiotherapy.<br>* Other names: Dynamic contrast-enhanced magnetic resonance imaging;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | To determine the efficacy of combining lapatinib and radiotherapy in terms of Progression-free survival (PFS) in patients with locally advanced HNSCC who cannot tolerate concurrent chemoradiotherapy. Progression-free survival is defined is the time from starting treatment to the time of first documented tumor progression or death due to any cause, which ever occurs first. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST V1.0) as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | 2 year PFS: PFS at 2 yrs after study enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival. | Overall survival is the time from starting treatment until death due to any cause. For subjects who do not die, time to death will be censored at the time of last contact. | Two years survival rate after study enrollment |