Study of Sorafenib/Cetuximab in Head and Neck Cancer

Study Overview
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Brief Summary
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In this Phase I B/II trial, we seek to determine the safety and efficacy of sorafenib with standard dose cetuximab in the treatment of patients with Recurrent and /or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN).

Detailed Description
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This is a non-randomized phase I B/II trial enrolling 43 patients with recurrent and/or metastatic SCCHN who are not candidates for surgical salvage or definitive radiation. Subjects will receive Cetuximab and sorafenib until disease progression. Cetuximab will be given at standard approved dose: 400 mg/m2 loading dose followed by 250 mg/m2 weekly. Sorafenib will be given 200 mg twice daily oral, continuous dosing to the 6 patients in cohort 1. If less than 3 patients experience dose limiting toxicities (DLT) at the 200mg BID dose, then 6 patients will be accrued at the 400mg BID dose level and toxicities will again be examined. Sorafenib will be given 400 mg twice daily oral, continuous dosing to the patients in cohort 2. One cycle equals 28 days. Tumor assessment will be performed every 8 weeks. Treatment continues until disease progression or unacceptable side effects. Participating subjects will be asked to take part in an optional correlative study to provide previously archived diagnostic or therapeutic tumor samples obtained during the course of their routine medical care for their cancer of the head/neck. The optional tissue repository project is Duke University Health System (DUHS) Institutional Review Board (IRB) approved (eIRB # 11138 / Tissue Acquisition Protocol for Analysis of Effects of Novel Chemotherapeutic Compounds). Subjects will be asked to sign a separate consent form to participate in the tissue collection study.

Official Title
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Sorafenib and Cetuximab in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN):a Phase I B/II Trial

Conditions
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Squamous Cell Cancer

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed squamous cell carcinoma of the head and neck Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria Age > 18 years old Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 Adequate bone marrow, liver and renal function as assessed by the following: Hemoglobin > 9.0 g/dl Absolute neutrophil count (ANC) > 1,500/mm3 Platelet count > 100,000/mm3 Total bilirubin < 1.5 times upper limit of normal (ULN) Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) < 2.5 times the ULN ( < 5 x ULN for patients with liver involvement) Creatinine < 1.5 times ULN Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib. International normalized ratio (INR) < 1.5 or a Prothrombin Time / Partial thromboplastin time (PT/PTT) within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. - For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable. Exclusion Criteria: Patients must not be candidates for potentially curative complete surgical resection or definitive radiation. (Patients may have received prior chemotherapy as part of definitive chemoradiotherapy and/or for recurrent/metastatic disease) Cardiac disease: Congestive heart failure > class II New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. Active clinically serious infection > Common Terminology Criteria for Adverse events (CTCAE) Grade 2. Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 (symptomatic and requiring medical intervention) within 4 weeks of first dose of study drug. Any other hemorrhage/bleeding event > CTCAE Grade 3 (bleeding requiring blood transfusion or intervention with endoscopy or surgery) within 4 weeks of first dose of study drug. Serious non-healing wound, ulcer, or bone fracture. Evidence or history of bleeding diathesis or coagulopathy Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug. Use of St. John's Wort or rifampin (rifampicin). Known or suspected allergy to sorafenib or any agent given in the this trial. Any malabsorption problem. Previous therapy with cetuximab for the treatment of recurrent and/or metastatic SCCHN. Previous therapy with cetuximab during definitive radiation therapy for locally advanced SCCHN is permitted so long as relapse of SCCHN occurred at least > 6 months (180 days) from the end of cetuximab therapy. Previous therapy with sorafenib, sunitinib or another small molecule known to inhibit the vascular endothelial growth factor receptors.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cetuximab + sorafenib<br>Cetuximab will be given at standard approved dose: 400 mg/m2 loading dose followed by 250 mg/m2 weekly. Sorafenib will be given at 200mg/m2 twice daily. | Drug: Sorafenib<br>* Phase 1 - Dose level 1 : Sorafenib will be given 200 mg twice daily oral, Phase 1 - Dose level 2 : Sorafenib will be given 400 mg twice daily oral, Phase 2 : Sorafenib will be given at the maximum tolerated dose from Phase 1<br>* Other names: Nexavar;Drug: Cetuximab<br>* Cetuximab will be given at standard approved dose: 400 mg/m2 loading dose followed by 250 mg/m2 weekly.<br>* Other names: Erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 - Maximum Tolerated Dose (MTD) of Sorafenib Administered With Cetuximab (400 mg/m2 Loading Dose Followed by 250 mg/m2 Weekly) | The MTD is based upon dose-limiting (DLTs) experienced during Cycle 1 of treatment. The MTD is the maximum dose level at which 0/6 or 1/6 patients experience DLT. Using Common Toxicity Criteria for Adverse EVents (CTCAE) version 3.0, DLTs are defined as any Grade 4 hematologic toxicity, or Grade 3 or 4 non-hematologic toxicity. A DLT will not be considered to have occurred in the case of a grade 3 or 4 allergic reaction due to cetuximab. | Cycle 1 (28 Days) | 
| Tumor Control Rate | The proportion of patients for whom the best overall response is complete response (CR), partial response (PR) or stable disease (SD). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. If follow-up assessments are not available, the best overall response is unevaluable. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Survival | Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive. | 5 years | 
| Median Progression-Free Survival (PFS) | Time in months from the start of study treatment to the date of first progression (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, or death due to any cause. Per RECIST, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression. | 5 years | 
| Phase 2 - Mean Change From Baseline in Quality of Life - Functional Assessment of Cancer Therapy - Head and Neck (FACT-H&N) | The outcome measure is the mean change in the Trial Outcome Index (TOI) between baseline and each follow-up assessment measured by the FACT-H&N. The instrument consists of 39 items to assess physical (PWB), social and family (SWB), emotional (EWB), functional well-bing (FWB) and additional head and neck specific concerns (HNCS). Using a 5-point Likert type scale, responses to individual items range from 0 (not at all) to 4 (Very Much) with higher scores indicating better quality of life. The TOI is the sum of PWB (7 items), FWB (7 items) and HNCS scores (12 items). TOI ranges from 0 to 140. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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squamous cell cancer, head and neck