A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine if the combination of two new drugs, cetuximab (Erbitux) and bevacizumab (Avastin) can increase the effectiveness of treatment for head and neck cancer. Cetuximab has recently been approved by the FDA for head and neck cancer (that is locally or regionally advanced) when used in combination with radiation therapy. Cetuximab is also approved by the FDA for the treatment of colorectal cancer

Detailed Description
-----------------
Approximately 40,000 new cases of head and neck cancer are diagnosed annually in the United States 1. Squamous cell carcinomas account for more than 90% of head and neck cancer cases. Patients with squamous cell carcinoma of the head and neck (HNSCC) usually present with locoregionally advanced disease. Initial presentation with distant metastasis may occur in about 10% of all patients. However, recurrence of disease either in local or distant sites after potentially curative treatment with surgery, radiation, and/or chemotherapy occurs in more than 50% of patients. Therefore, the majority of patients with HNSCC develop recurrent or metastatic disease during the course of their illness. These patients have a dismal prognosis with a median survival of 6-9 months 2-4. Active single agents in head and neck squamous cell carcinoma include methotrexate, bleomycin, cisplatin, carboplatin, 5-FU, paclitaxel, docetaxel, and CPT-11. A small randomized study showed that cisplatin monotherapy prolongs survival compared with best supportive care 5. Response rates for single agents range between 10-40% 2, 4, 6, 7. Combination chemotherapy with platinum agents, in spite of achieving higher response rates (about 30% in phase III trials), has not been shown to produce a survival benefit compared to single agents in randomized comparisons in recurrent/metastatic head and neck cancer 2, 4.

Official Title
-----------------
A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer

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

Intervention / Treatment
-----------------
* Drug: Cetuximab
* Drug: Bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Eligibility Criteria Patients must have histologically or cytologically confirmed Squamous Cell Cancer of the Head and Neck either (a) metastatic (i.e. American Joint Committee on Cancer Staging System, 6th edition, stage IVC) or (b) recurrent, judged incurable by surgery or radiation. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with CT scan). RECIST criteria will be used (see section 9). Therapeutic history in conformance with the following: No more than one prior adjuvant/neoadjuvant chemotherapy and/or concomitant chemoradiotherapy regimen that may have included biologic/targeted agent. No more than one prior regimen (chemotherapy or biologic/targeted) for recurrent/metastatic disease ECOG performance status of 0-2 (Karnofsky > 60%; see Appendix A). Patients must have normal organ and marrow function as defined below: absolute neutrophil count > 1,000/L platelets > 75,000/L total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) 5 X institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio (see Appendix). For UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be <1000 mg for patient enrollment. Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion - a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is calculated using on of the following formula: [urine protein]/[urine creatinine] - if both protein and creatinine are reported in mg/Dl [(urine protein) x0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L All patients should have baseline tumor tissue available for EGFR determination (therapeutic target of cetuximab) and biomarker studies. Patients without available tissue at baseline may undergo tumor biopsy. Patients who provide consent and have accessible tumors will have a repeat biopsy 14 days (an interval between 12-16 days is acceptable) post initiation of therapy. Priority for study entry will be given to patients with easily accessible tumor and who consent to repeat biopsy. Study entry will not be restricted to patients who agree to further biopsies. If a patient enrolls on study and later refuses biopsy (excluding diagnostic), he/she may remain on study. No prior treatment with cetuximab or bevacizumab or other EGFR or VEGF targeting agents. Patients should not have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) and biologic/targeted agents within 3 weeks. At least 3 months should have elapsed after prior therapy with monoclonal antibodies. At least 3 weeks should have elapsed from prior radiotherapy. Patients must have no history of gross hemoptysis (defined as bright red blood of a ½ teaspoon or more) or coagulopathy. Patients with history of major tumor-related bleeding that is not controlled despite locoregional treatment or at high risk of recurrent tumor-related bleeding will be excluded. Patients should not have a history of thrombosis (e.g. pulmonary embolism or deep venous thrombosis) and should not be on therapeutic anticoagulation (prophylactic use of warfarin 1 mg per day is allowed) and INR should be less than 1.5 at registration. Patients with history of hypertension must be well-controlled (≤150/100) on a stable regimen of anti-hypertensive therapy. Patients with tumors that invaded major vessels (e.g. the carotid) as shown unequivocally by imaging studies will be excluded due to the possibility of increased risk for tumor bleeding with bevacizumab therapy. No major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment, or anticipation of need for major surgical procedure during the course of the study. No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to registration. No serious non-healing wound, ulcer, or bone fracture. No unstable angina or myocardial infarction within the previous 6 months; no uncontrolled hypertension; no symptomatic congestive heart failure; no serious cardiac arrhythmia requiring medication; no clinically significant peripheral vascular disease; no history of any CNS cerebrovascular ischemia or stroke within the last 6 months; no active serious infection. No other coexisting medical condition that would preclude full compliance with the study. Patients may not be receiving any other investigational agents. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because of increased risks with bevacizumab. Patients should not have a history of prior severe infusion reaction to a monoclonal antibody. Patients with known hypersensitivity of Chinese hamster ovary cell products or other recombinant human antibodies. No history of prior malignancy, with the exception of curatively treated squamous cell or basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year disease-free interval. Age > 18 years. Because no dosing or adverse event data are currently available on the use of cetuximab and bevacizumab in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric single-agent trials, if applicable. Ability to understand and the willingness to sign a written informed consent document. Pregnant women are excluded from this study because cetuximab and bevacizumab have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cetuximab and bevacizumab, breastfeeding should be discontinued if the mother is treated with cetuximab and bevacizumab. The effects of cetuximab and bevacizumab on the developing human fetus at the recommended therapeutic dose are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while in this study, she should inform her treating physician immediately. HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible drug interactions with cetuximab and bevacizumab. Appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated. Inclusion of Women and Minorities Both men and women and members of all ethnic groups are eligible for this trial. The proposed study population is illustrated in the table below. Inclusion of Women in Plan: The gender distribution of our head and neck cancer patients is detailed in the table below. All efforts are made to recruit women patients with head and neck cancer to the University of Pittsburgh Medical Center.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 98 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: Cetuximab plus bevacizumab<br>Cetuximab plus bevacizumab | Drug: Cetuximab<br>* Cetuximab 400 mg/m2 IV over 120 minutes on day 1 of cycle 1 ONLY Cetuximab dose will be 250 mg/m2 IV over 60 minutes weekly on ALL subsequent administrations<br>* Other names: Erbitux, C225;Drug: Bevacizumab<br>* Once every 3 weeks, 15 mg/kg of bevacizumab will be given by IV infusion after cetuximab has been given<br>* Other names: (rhuMAb VEGF, Avastin) (NSC 704865; IND 7921);|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is the percentage of patients whose cancer shrunk or disappeared after study treatment. ORR was determined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI) : Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Progressive Disease (PD): at least a 20% increase in the sum of the 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; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is the length of time during and after treatment that patients are alive with the disease but it does not get worse. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI), Progressive Disease is defined as at least a 20% increase in the sum of the 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. | Up to 5 years | 
| Overall Survival (OS) | The length of time from the start of study/treatment that diagnosed patients are still alive. | Up to 5 years | 
| Change in Serum Cytokine Concentrations | Ratio of serum cytokines concentration after treatment with cetuximab and bevacizumab to baseline serum cytokines concentration, in picogram/milliliter (pg/ml) for 13 different cytokines. [post-treatment (pg/ml) / baseline (pg/ml)] | Up to 5 years | 
| Disease Control Rate (DCR) ((Clinical Benefit Rate (CBR)) | Disease Control Rate (DCR) (or Clinical Benefit Rate (CBR)), is defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to cetuximab and bevacizumab. DCR = number of patients with (at least) partial response or stable disease / total number of evaluable patients | At 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
head and neck cancer, cetuximab, bevacizumab, squamous cell carcinoma, SCCHN, Squamous Cell Carcinoma of the Head and Neck