Chemotherapy With or Without Bevacizumab in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Tracking Information
First Submitted Date ICMJE	December 28, 2007
First Posted Date ICMJE	January 9, 2008
Last Update Posted Date	March 2, 2018
Actual Study Start Date ICMJE	August 8, 2008
Estimated Primary Completion Date	February 28, 2018 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: August 4, 2014)	Overall survival [ Time Frame: Time from randomization to date of death from any cause, censored at date of last contact, assessed up to 5 years ]; Interim analyses comparing overall survival between the two arms using long-rank tests will be performed. At each analysis, critical values for the long-rank test will be calculated using a truncated Lan-Demets error spending rate function corresponding to the O'Brien-Fleming boundary.
Original Primary Outcome Measures ICMJE; (submitted: December 28, 2007)	Overall survival
Change History	Complete list of historical versions of study NCT00588770 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: April 9, 2015)	Comorbidities [ Time Frame: Up to 5 years ]The impact of comorbidities on endpoints will be assessed.; Incidence of toxicity as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]One-sided Fisher's exact tests with alpha of 0.05 will be used at each interim analysis, and no adjustment will be made for multiple comparisons.; Objective response rates [ Time Frame: Up to 5 years ]The sum of the longest diameters of all target lesions will be calculated at baseline and reported as the baseline sum longest diameter. The sum longest diameter will be used to characterize the objective tumor response.; Progression-free survival [ Time Frame: From the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression, assessed up to 5 years ]
Original Secondary Outcome Measures ICMJE; (submitted: December 28, 2007)	Toxicity; Objective response rates; Progression-free survival; Impact of comorbidity
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Chemotherapy With or Without Bevacizumab in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Official Title ICMJE	A Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer
Brief Summary	This randomized phase III trial studies chemotherapy to see how well it works with or without bevacizumab in treating patients with head and neck squamous cell carcinoma that has come back (recurrent) or that has spread to other parts of the body (metastatic). Drugs used in chemotherapy, such as docetaxel, cisplatin, carboplatin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Bevacizumab may also make tumor cells more sensitive to chemotherapy and stop the growth of head and neck cancer by blocking blood flow to the tumor. It is not yet known whether combination chemotherapy is more effective when given with or without bevacizumab in treating patients with head and neck squamous cell carcinoma.
Detailed Description	PRIMARY OBJECTIVES: I. To compare the overall survival of patients with recurrent or metastatic head and neck cancer treated with standard platinum-based chemotherapy with or without bevacizumab. SECONDARY OBJECTIVES: I. To assess toxicities with the addition of bevacizumab to each platinum-doublet (cisplatin/docetaxel, carboplatin/docetaxel, cisplatin/fluorouracil [5-FU], carboplatin/5-FU). II. To compare the objective response rates and the progression-free survival achieved with the above therapies. III. To collect blood samples before and after therapy for future correlative studies. IV. To collect tumor tissue samples available at baseline from prior diagnostic procedures for future correlative studies. OUTLINE: After the physician decides which chemotherapy doublet to use, patients are randomized to 1 of 2 treatment arms for that chemotherapy combination. ARM IA: Patients receive chemotherapy comprising docetaxel intravenously (IV) over 1 hour and cisplatin IV over 1-2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM IB: Patients receive bevacizumab IV over 30-90 minutes on day 1 and docetaxel and cisplatin as in Arm IA. ARM IIA: Patients receive docetaxel IV over 1 hour and carboplatin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM IIB: Patients receive bevacizumab as in arm IB and docetaxel and carboplatin as in Arm IIA. ARM IIIA: Patients receive cisplatin IV over 1-2 hours on day 1 and fluorouracil IV continuously on days 1-4. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM IIIB: Patients receive bevacizumab as in Arm IB and cisplatin and fluorouracil as in Arm IIIA. ARM IVA: Patients receive carboplatin IV over 30 minutes on day 1 and fluorouracil IV continuously on days 1-4. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM IVB: Patients receive bevacizumab as in Arm IB and carboplatin and fluorouracil as in Arm IVA. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Study Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Recurrent Hypopharyngeal Squamous Cell Carcinoma; Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary; Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Recurrent Salivary Gland Carcinoma; Salivary Gland Squamous Cell Carcinoma; Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary; Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IV Major Salivary Gland Cancer AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVA Laryngeal Verrucous Carcinoma AJCC v7; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Major Salivary Gland Cancer AJCC v7; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVA Oral Cavity Cancer AJCC v6 and v7; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Verrucous Carcinoma AJCC v7; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Major Salivary Gland Cancer AJCC v7; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVB Oral Cavity Cancer AJCC v6 and v7; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Laryngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Laryngeal Verrucous Carcinoma AJCC v7; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVC Major Salivary Gland Cancer AJCC v7; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma AJCC v7; Stage IVC Oral Cavity Cancer AJCC v6 and v7; Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7; Tongue Carcinoma; Untreated Metastatic Squamous Cell Carcinoma to Neck With Occult Primary
Intervention ICMJE	Biological: Bevacizumab Given IV Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar FKB238 BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF; Drug: Carboplatin Given IV Other Names: Blastocarb Carboplat Carboplatin Hexal Carboplatino Carbosin Carbosol Carbotec CBDCA Displata Ercar JM-8 Nealorin Novoplatinum Paraplatin Paraplatin AQ Paraplatine Platinwas Ribocarbo; Drug: Cisplatin Given IV Other Names: Abiplatin Blastolem Briplatin CDDP Cis-diammine-dichloroplatinum Cis-diamminedichloridoplatinum Cis-diamminedichloro Platinum (II) Cis-diamminedichloroplatinum Cis-dichloroammine Platinum (II) Cis-platinous Diamine Dichloride Cis-platinum Cis-platinum II Cis-platinum II Diamine Dichloride Cismaplat Cisplatina Cisplatinum Cisplatyl Citoplatino Citosin Cysplatyna DDP Lederplatin Metaplatin Neoplatin Peyrone's Chloride Peyrone's Salt Placis Plastistil Platamine Platiblastin Platiblastin-S Platinex Platinol Platinol- AQ Platinol-AQ Platinol-AQ VHA Plus Platinoxan Platinum Platinum Diamminodichloride Platiran Platistin Platosin; Drug: Docetaxel Given IV Other Names: Docecad RP56976 Taxotere Taxotere Injection Concentrate; Drug: Fluorouracil Given IV Other Names: 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-FU AccuSite Carac Fluoro Uracil Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Ribofluor Ro 2-9757 Ro-2-9757; Other: Laboratory Biomarker Analysis Correlative studies
Study Arms	Active Comparator: Arm IA (docetaxel, cisplatin) Patients receive docetaxel IV over 1 hour and cisplatin IV over 1-2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Interventions: Drug: Cisplatin Drug: Docetaxel Other: Laboratory Biomarker Analysis; Experimental: Arm IB (docetaxel, cisplatin, bevacizumab) Patients receive bevacizumab IV over 30-90 minutes on day 1 and docetaxel and cisplatin as in Arm IA. Interventions: Biological: Bevacizumab Drug: Cisplatin Drug: Docetaxel Other: Laboratory Biomarker Analysis; Active Comparator: Arm IIA (docetaxel, carboplatin) Patients receive docetaxel IV over 1 hour and carboplatin IV over 30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Interventions: Drug: Carboplatin Drug: Docetaxel Other: Laboratory Biomarker Analysis; Experimental: Arm IIB (docetaxel, carboplatin, bevacizumab) Patients receive bevacizumab as in Arm IB and docetaxel and carboplatin as in Arm IIA. Interventions: Biological: Bevacizumab Drug: Carboplatin Drug: Docetaxel Other: Laboratory Biomarker Analysis; Active Comparator: Arm IIIA (cisplatin, fluorouracil) Patients receive cisplatin IV over 1-2 hours on day 1 and fluorouracil IV continuously on days 1-4. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Interventions: Drug: Cisplatin Drug: Fluorouracil Other: Laboratory Biomarker Analysis; Experimental: Arm IIIB (cisplatin, fluorouracil, bevacizumab) Patients receive bevacizumab as in Arm IB and cisplatin and fluorouracil as in Arm IIIA. Interventions: Biological: Bevacizumab Drug: Cisplatin Drug: Fluorouracil Other: Laboratory Biomarker Analysis; Active Comparator: Arm IVA (carboplatin, fluorouracil) Patients receive carboplatin IV over 30 minutes on day 1 and fluorouracil IV continuously on days 1-4. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Interventions: Drug: Carboplatin Drug: Fluorouracil Other: Laboratory Biomarker Analysis; Experimental: Arm IVB (carboplatin, fluorouracil, bevacizumab) Patients receive bevacizumab as in Arm IB and carboplatin and fluorouracil as in Arm IVA. Interventions: Biological: Bevacizumab Drug: Carboplatin Drug: Fluorouracil Other: Laboratory Biomarker Analysis
Publications *	Not Provided
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Active, not recruiting
Estimated Enrollment ICMJE; (submitted: December 28, 2007)	400
Original Enrollment ICMJE	Same as current
Study Completion Date	Not Provided
Estimated Primary Completion Date	February 28, 2018 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Patients must have histologically or cytologically confirmed squamous cell cancer of the head and neck (SCCHN), from any primary site, including unknown primary cancers of the head and neck; patient must not have nasopharyngeal carcinoma of histologic types World Health Organization (WHO) 2 or 3 or squamous cell carcinoma that originated in the skin; Patients must have SCCHN that is either (a) recurrent, judged incurable by surgery or radiation or (b) metastatic; NOTE: Patients who refuse radical resection for recurrent disease are eligible; NOTE: A second primary squamous cell carcinoma of the head and neck is allowed if eligibility is based on a recurrent or metastatic first primary squamous cell carcinoma of the head and neck; No prior chemotherapy or biologic/molecular targeted therapy for recurrent or metastatic SCCHN Patients may have received one regimen of induction, concomitant chemoradiotherapy and/or adjuvant chemotherapy as part of initial potential curative therapy but must not have received prior chemotherapy for recurrent or metastatic disease A minimum of 4 months is required between last dose of chemotherapy or chemoradiotherapy and study treatment; in addition patients must be progression-free for at least 4 months after completion of chemotherapy or chemoradiotherapy or radiation plus cetuximab given with a curative intent; (cetuximab therapy: 4 months is required between last dose of chemotherapy or chemoradiotherapy and study treatment if part of concurrent regimen, 8 weeks if part of adjuvant regimen post radiation) Patients having progression after 2 cycles of induction chemotherapy are not eligible for the study; No prior bevacizumab is allowed; A maximum of one prior radiotherapy regimen, curative or palliative, to the head and neck is allowed; if the radiation is combined with chemotherapy and/or cetuximab, a minimum of 4 months must elapse between the end of radiotherapy and registration; if the radiation is given alone, a minimum of 8 weeks must elapse between the end of radiotherapy and registration; a minimum of 3 weeks must elapse between prior radiation to other areas and registration; Patients must not be receiving any other investigational agent while on the study; Eastern Cooperative Oncology Group (ECOG) performance status of 0-1; Patients must have recovered to grade 1 or better from any acute effects of prior surgery, chemotherapy, or radiation therapy, and should be > 4 weeks post surgery; chronic late xerostomia, speech and swallowing abnormalities resulting from prior radiation or surgery are permitted if nutritional status is stable; Patients must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST); baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to randomization; disease in previously irradiated sites is considered measurable if there has been unequivocal disease progression or biopsy-proven residual carcinoma following radiation therapy; persistent disease after radiotherapy must be biopsy proven at least 8 weeks after completion of radiation therapy; (radiographic findings are acceptable providing that clear-cut measurements can be made); Absolute neutrophil count (ANC) >= 1500/mm^3; Hemoglobin (Hgb) >= 8.0 g/dL; Platelet count >= 100,000/mm^3; Creatinine clearance of >= 60 ml/min; creatinine clearance may be measured or calculated; if calculating, creatinine clearance, use the Cockroft-Gault formula; Total bilirubin within normal limits (must be obtained =< 2 weeks prior to randomization); Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) must be within the range allowing for eligibility Alkaline phosphatase normal AND AST or ALT =< 5 x upper limit of normal (ULN) Alkaline phosphatase > 1 but =< 2.5 x ULN AND AST or ALT > 1 but =< 1.5 x ULN Alkaline phosphatase > 2.5 but =< 5 x ULN AND AST or ALT normal; Alkaline phosphatase must be within the range allowing for eligibility; Urine dipstick must be =< 0-1+ within 2 weeks (14 days) of randomization; if urine dipstick result is > 1+, a calculation of urine protein creatinine (UPC) ratio is required; patients must have a UPC ratio < 1.0 to participate in the study; 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; No known brain metastases; Patients who meet the following criteria will be excluded: Tumors that invade major vessels (e.g. the carotid) as shown unequivocally by imaging studies Central (i.e. within 2 cm from the hilum) lung metastases that are cavitary as shown unequivocally by imaging studies Any prior history of bleeding related to the current head and neck cancer History of gross hemoptysis (bright red blood of 1/2 teaspoon or more per episode of coughing) =< 3 months prior to enrollment; No history of coagulopathy or hemorrhagic disorders; Patients should not have a history of thrombosis (e.g. pulmonary embolism or deep venous thrombosis) currently requiring therapeutic anticoagulation (prophylactic use of warfarin 1 mg per day is allowed) and international normalized ratio (INR) should be < 1.5 at registration; Patients must not be receiving chronic daily treatment with aspirin (> 325 mg/day) or non-steroidal anti-inflammatory agents (NSAID's) known to inhibit platelet function; the use of anti-platelet agents (e.g. dipyridamole [Persantine], ticlopidine [Ticlid], clopidogrel [Plavix]) is allowed only if patient is not receiving aspirin or NSAID's known to inhibit platelet function; No hypercalcemia related to head and neck cancer; Patients with a prior history of squamous cell or basal carcinoma of the skin or in situ cervical cancer must have been curatively treated; patients with a history of other prior malignancy must have been treated with curative intent and must have remained disease-free for 3 years post diagnosis; No current peripheral neuropathy >= grade 2 at time of randomization; Patients must not have any co-existing condition that would preclude full compliance with the study; No prior history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80, if the physician's choice of chemotherapy regimen is docetaxel; All patients must have blood pressure =< 150/90 =< 2 weeks prior to randomization; patients with history of hypertension must be well-controlled upon study entry (=< 150/90) on a stable regimen of anti-hypertensive 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 unstable angina or myocardial infarction within the previous 6 months; no symptomatic congestive heart failure, New York Heart Association (NYHA) grade II or greater; no history of aortic dissection or presence of aneurysm > 6 cm (or at high risk for rupture); no serious cardiac arrhythmia requiring medication (history of chronic atrial fibrillation or other atrial arrhythmia with controlled rate on medication is allowed); no clinically significant peripheral vascular disease manifested by intermittent claudication or need for vascular intervention; no history of aortic dissection; no history of any central nervous system (CNS) cerebrovascular ischemia or stroke within the last 6 months; no active serious infection; Patients should not have prior history of a serious human anti-human antibody (HAHA) reaction; patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies are not eligible; Women must not be pregnant or breast feeding; pregnant women are excluded from this study; women of child-bearing potential and men must agree to total abstinence or to use adequate 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; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy; Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral therapy are excluded from the study; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated; No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to registration
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Puerto Rico, South Africa, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00588770
Other Study ID Numbers ICMJE	NCI-2009-00507; NCI-2009-00507 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000582533; E1305; E1305 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); E1305 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract ); U10CA021115 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Cancer Institute (NCI)
Study Sponsor ICMJE	National Cancer Institute (NCI)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Athanassios (Ethan) Argiris ECOG-ACRIN Cancer Research Group
PRS Account	National Cancer Institute (NCI)
Verification Date	February 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP