Chemotherapy With or Without Bevacizumab in Treating Patients With Recurrent or Metastatic Head and Neck Cancer

• Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  The rates of grade 3-5 bleeding events will be monitored continuously and the difference between the treatment arms. A true rate of grade 5 bleeding events of 1-2% would be considered acceptable and is expected. One-sided Fisher's exact tests with alpha of 0.05 will be used at each interim analysis, and no adjustments will be made for multiple comparisons.
• Objective response rates [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
• Impact of comorbidities on endpoints [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

• Toxicity [ Designated as safety issue: Yes ]
• Objective response rate [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]
• Impact of comorbidity [ Designated as safety issue: Yes ]

This randomized phase III trial is studying chemotherapy to see how well it works with or without bevacizumab in treating patients with recurrent or metastatic head and neck cancer. 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 or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. 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 cancer.

PRIMARY OBJECTIVES:

I. To compare the overall survival of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with standard platinum-based chemotherapy with or without bevacizumab.

SECONDARY OBJEC TIVES:

I. To assess toxicities with the addition of bevacizumab to each platinum-doublet (cisplatin/docetaxel, carboplatin/docetaxel, cisplatin/fluorouracil, carboplatin/fluorouracil.

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 to1 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. Treatment repeats 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. Treatment repeats 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 over days 1-4. Treatment repeats 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 over days 1-4. Treatment repeats 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 3-6 months for 5 years.

• Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma
• Recurrent Metastatic Squamous Neck Cancer With Occult Primary
• Recurrent Salivary Gland Cancer
• Recurrent Squamous Cell Carcinoma of the Hypopharynx
• Recurrent Squamous Cell Carcinoma of the Larynx
• Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity
• Recurrent Squamous Cell Carcinoma of the Nasopharynx
• Recurrent Squamous Cell Carcinoma of the Oropharynx
• Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
• Recurrent Verrucous Carcinoma of the Larynx
• Recurrent Verrucous Carcinoma of the Oral Cavity
• Salivary Gland Squamous Cell Carcinoma
• Stage IV Salivary Gland Cancer
• Stage IV Squamous Cell Carcinoma of the Hypopharynx
• Stage IV Squamous Cell Carcinoma of the Larynx
• Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity
• Stage IV Squamous Cell Carcinoma of the Nasopharynx
• Stage IV Squamous Cell Carcinoma of the Oropharynx
• Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity
• Stage IV Verrucous Carcinoma of the Larynx
• Stage IV Verrucous Carcinoma of the Oral Cavity
• Tongue Cancer
• Untreated Metastatic Squamous Neck Cancer With Occult Primary

• Drug: docetaxel
  Given IV
  Other Names:

  • RP 56976
  • Taxotere
  • TXT
• Drug: cisplatin
  Given IV
  Other Names:

  • CACP
  • CDDP
  • CPDD
  • DDP
• Drug: carboplatin
  Given IV
  Other Names:

  • Carboplat
  • CBDCA
  • JM-8
  • Paraplat
  • Paraplatin
• Drug: fluorouracil
  Given IV
  Other Names:

  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
• Biological: bevacizumab
  Given IV
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF

• Active Comparator: Arm IA (docetaxel, cisplatin)
  Patients receive docetaxel IV over 1 hour and cisplatin IV over 1-2 hours on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: docetaxel
  • Drug: cisplatin
• 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:

  • Drug: docetaxel
  • Drug: cisplatin
  • Biological: bevacizumab
• Active Comparator: Arm IIA (docetaxel, carboplatin)
  Patients receive docetaxel IV over 1 hour and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: docetaxel
  • Drug: carboplatin
• Experimental: Arm IIB (docetaxel, carboplatin, bevacizumab)
  Patients receive bevacizumab as in arm IB and docetaxel and carboplatin as in arm IIA.
  Interventions:

  • Drug: docetaxel
  • Drug: carboplatin
  • Biological: bevacizumab
• Active Comparator: Arm IIIA (cisplatin, fluorouracil)
  Patients receive cisplatin IV over 1-2 hours on day 1 and fluorouracil IV continuously over days 1-4. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: cisplatin
  • Drug: fluorouracil
• Experimental: Arm IIIB (cisplatin, fluorouracil, bevacizumab)
  Patients receive bevacizumab as in arm IB and cisplatin and fluorouracil as in arm IIIA.
  Interventions:

  • Drug: cisplatin
  • Drug: fluorouracil
  • Biological: bevacizumab
• Active Comparator: Arm IVA (carboplatin, fluorouracil)
  Patients receive carboplatin IV over 30 minutes on day 1 and fluorouracil IV continuously over days 1-4. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: carboplatin
  • Drug: fluorouracil
• Experimental: Arm IVB (carboplatin, fluorouracil, bevacizumab)
  Patients receive bevacizumab as in arm IB and carboplatin and fluorouracil as in arm IVA.
  Interventions:

  • Drug: carboplatin
  • Drug: fluorouracil
  • Biological: bevacizumab

Inclusion Criteria:

• Histologically or cytologically confirmed squamous cell carcinoma of the head and neck (SCCHN) from any primary site, including unknown primary cancers of the head and neck

  • No nasopharyngeal carcinoma of histologic types World Health Organization (WHO) 2 or 3
  • No squamous cell carcinoma that originated in the skin

• Recurrent disease, incurable disease as determined by surgery or radiation, or metastatic disease

  • A second primary SCCHN allowed if eligibility is based on a recurrent or metastatic first primary SCCHN
• Patients who refuse radical resection for recurrent disease are eligible

• Patients must have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)

  • Disease in previously irradiated sites is considered measurable if there has been unequivocal disease progression or biopsy-proven residual carcinoma after radiotherapy
  • Persistent disease after radiotherapy must be biopsy proven at least 8 weeks after completion of radiotherapy (radiographic findings are acceptable providing that clear cut measurements can be made)

• Patients must be progression-free for at least 6 months after completion of chemotherapy or chemoradiotherapy or radiotherapy plus cetuximab given as part of initial potential curative therapy (if received such prior therapy)

  • At least 6 months since completion of prior concurrent radiotherapy plus cetuximab (8 weeks for cetuximab given as part of adjuvant regimen post radiotherapy)
  • Patients having progression after 2 courses of induction chemotherapy are not eligible
• No tumors that invade major vessels (e.g., the carotid) as shown unequivocally by imaging studies
• No known brain metastases
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Hemoglobin >= 8.0 g/dL
• Platelet count >= 100,000/mm^3
• Creatinine clearance >= 60 mL/min
• Total bilirubin normal

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and alkaline phosphatase must meet one of the following criteria:

  • 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
• 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
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

• Patients who meet the following criteria will be excluded due to the possibility of increased risk for tumor bleeding with bevacizumab therapy:

  • 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 0.5 teaspoon or more per episode of coughing) =< 3 months prior to enrollment
• No history of coagulopathy or hemorrhagic disorders
• No history of thrombosis (e.g., pulmonary embolism or deep venous thrombosis) currently requiring therapeutic anticoagulation (prophylactic use of warfarin 1 mg/day is allowed)
• International normalized ratio (INR) < 1.5 at registration
• No hypercalcemia related to head and neck cancer

• Patients with a prior history of squamous cell or basal cell carcinoma of the skin or in situ carcinoma of the cervix 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 5 years post diagnosis
• No current peripheral neuropathy >= grade 2
• Patients must not have any co-existing condition that would preclude full compliance with the study
• No history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80 (if the physician's choice of chemotherapy is docetaxel)

• Patients must have a blood pressure (BP) =< 150/90 mm Hg within 2 weeks prior to randomization

  • Patients with a history of hypertension must be well-controlled upon study entry (BP =< 150/90 mm Hg) on a stable regimen of anti-hypertensive therapy
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to registration
• No significant traumatic injury within the past 28 days
• No serious nonhealing wound, ulcer, or bone fracture
• No unstable angina or myocardial infarction within the past 6 months
• No symptomatic congestive heart failure or New York Heart Association (NYHA) class II-IV heart disease
• 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 any central nervous system (CNS) cerebrovascular ischemia or stroke within the past 6 months
• No active serious infection
• No 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
• Chronic latex xerostomia, speech and swallowing abnormalities, resulting from prior radiation or surgery, allowed provided nutritional status is stable
• No other prior malignancy except curatively treated squamous cell or basal carcinoma of the skin, in situ cervical cancer, or malignancy for which the patient has been curatively treated and remains disease-free for the past 3 years
• No concurrent bisphosphonates for bone metastasis unless initiated > 3 months before study entry
• Patients must have recovered to grade 1 or better from the effects of any prior surgery, chemotherapy, or radiotherapy AND > 4 weeks post-surgery
• 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
• No prior bevacizumab

• No prior chemotherapy or biologic/molecular-targeted therapy for recurrent or metastatic SCCHN

  • Patients may have received one regimen of induction, concurrent chemoradiotherapy, and/or adjuvant chemotherapy as part of initial potential curative therapy

    • A minimum of 6 months is required between last dose of chemotherapy or chemoradiotherapy and study treatment
• No major surgical procedure or open biopsy within 28 days prior to study enrollment, or anticipation of need for major surgical procedure during the course of the study
• More than 4 weeks since prior surgery
• No other concurrent investigational agent

• Patients must not be receiving chronic daily treatment with aspirin (> 325 mg/day) or nonsteroidal anti-inflammatory agents (NSAIDs) known to inhibit platelet function

  • The use of anti-platelet agents (e.g., dipyridamole [Persantine], ticlopidine [Ticlid], or clopidogrel [Plavix]) is allowed only if patient is not receiving aspirin or NSAIDs known to inhibit platelet function
• No human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
• No other concurrent chemotherapy, immunotherapy, antitumor hormonal therapy (excluding contraceptives and replacement steroids), radiotherapy, or experimental medications
• No concurrent amifostine