A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer
|First Received Date ICMJE||December 7, 2006|
|Last Updated Date||June 1, 2016|
|Start Date ICMJE||September 2006|
|Primary Completion Date||February 2012 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||To Determine the Objective Response Rate (Primary Endpoint) With the Combination of Cetuximab Plus Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. [ Time Frame: 5 years ]
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.
|Original Primary Outcome Measures ICMJE
||1.1. To determine the objective response rate (primary endpoint) with the combination of cetuximab plus bevacizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma.|
|Change History||Complete list of historical versions of study NCT00409565 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||To Determine the Progression-free Survival and Overall Survival of Patients With Recurrent or Metastatic Head and Neck Cancer Treated With Cetuximab Plus Bevacizumab. [ Time Frame: 5 years ]
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. Duration of overall response: measured from the time measurement criteria are met for CR or PR until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since treatment started.
|Original Secondary Outcome Measures ICMJE
||1.2. To determine the progression-free survival and overall survival of patients with recurrent or metastatic head and neck cancer treated with cetuximab plus bevacizumab.|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer|
|Official Title ICMJE||A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer|
|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|
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.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Study Arms||Experimental: Cetuximab plus bevacizumab
Cetuximab plus bevacizumab
|Publications *||Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, Gyanchandani R, Blumenschein GR Jr, Chen HX, Grandis JR, Harari PM, Kies MS, Kim S. Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2013 Jan;24(1):220-5. doi: 10.1093/annonc/mds245.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||February 2012|
|Primary Completion Date||February 2012 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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
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||18 Years to 98 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00409565|
|Other Study ID Numbers ICMJE||05-087
NCI / CTEP Protocol # 7440
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||University of Pittsburgh|
|Study Sponsor ICMJE||University of Pittsburgh|
|Collaborators ICMJE||National Cancer Institute (NCI)|
|Information Provided By||University of Pittsburgh|
|Verification Date||May 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP