Cetuximab With or Without Tivantinib in Treating Patients With Head and Neck Cancer That Is Recurrent, Metastatic, or Cannot Be Removed by Surgery
Cetuximab With or Without Tivantinib in Treating Patients With Head and Neck Cancer That Is Recurrent, Metastatic, or Cannot Be Removed by Surgery
This randomized phase II trial studies how well cetuximab with or without tivantinib works in
 treating patients with head and neck cancer that has come back (recurrent), has spread to
 other places in the body (metastatic), or cannot be removed by surgery. Monoclonal
 antibodies, such as cetuximab, may interfere with the ability of tumor cells to grow and
 spread. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed
 for cell growth. It is not yet known whether cetuximab is more effective with or without
 tivantinib in treating patients with head and neck cancer.
PRIMARY OBJECTIVES:

 I. Response rate (comparing the cetuximab/ARQ 197 [tivantinib] combination with cetuximab
 single agent activity).

 SECONDARY OBJECTIVES:

 I. Continuous tumor shrinkage. II. Progression-free survival (PFS). III. Overall survival
 (OS). IV. Objectives I, II, and III above, as well as response rates, will be assessed and
 compared between treatment arms in the subgroup of patients with high mesenchymal epithelial
 transition factor (c-MET) expression, and/or high c-MET copy number.

 V. Single agent activity for ARQ 197 (tivantinib) in patients who have failed cetuximab.

 OUTLINE: Patients are randomized to 1 of 2 treatment arms.

 ARM I: Patients receive cetuximab intravenously (IV) over 60-120 minutes on days 1 and 15 and
 tivantinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 4 weeks in the
 absence of disease progression or unacceptable toxicity.

 ARM II: Patients receive cetuximab IV over 60-120 minutes on days 1 and 15. Patients who fail
 cetuximab as a single agent may receive single agent tivantinib PO BID on days 1-28. Courses
 repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up for 5 years.
Inclusion Criteria:

 -  Histologically/cytologically confirmed diagnosis of squamous cell carcinoma of head
 and neck origin not amenable to curative intent therapy; both human papillomavirus
 (HPV) positive (+) and HPV negative (-) are eligible, but status has to be known prior
 to randomization (although not required for consenting); any type of tissue based HPV
 assessment is acceptable (e.g. p16 immunohistochemistry [IHC] or HPV in situ
 hybridization [ISH]); if local HPV testing is not available slides can be sent to the
 University of Chicago for HPV testing; please note that p16 IHC is generally only
 considered to be accurate for oropharyngeal tumors

 -  Presence of measurable lesions (as per Response Evaluation Criteria in Solid Tumors
 [RECIST] 1.1); generally a >= 10 mm tumor lesion (in the longest diameter by computed
 tomography [CT] scan) or a lymph node >= 15 mm (short axis) is considered measurable
 disease when evaluated by CT scan (with a slice thickness no greater than 5 mm)

 -  Availability of tissue (10 tumor containing formalin-fixed, paraffin-embedded [FFPE]
 slides/sections)

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1

 -  Patients who have received cetuximab or another inhibitor of epidermal growth factor
 receptor (EGFR) in the curative intent treatment setting (e.g. with radiation or
 during induction chemotherapy [prior to definitive, curative intent therapy]) are
 eligible for the study

 -  Life expectancy of greater than 8 weeks

 -  Hemoglobin >= 9.0 g/dL

 -  Leukocytes >= 3,000/mcL

 -  Absolute neutrophil count >= 1,500/mcL

 -  Platelets >= 100,000/mcL

 -  Total bilirubin =< 1.5 x institutional upper limit of normal

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2.5 x institutional upper limit of normal

 -  Serum creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance
 >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

 -  Patients must be able to swallow ARQ 197 (tivantinib) by mouth, unless adequate data
 about administration by gastrostomy (G)-tube becomes available; tablets may be
 crushed, but must be taken orally

 -  Human immunodeficiency virus (HIV)-positive patients with normal immune function
 (cluster of differentiation [CD]4 count > 200) are eligible if there are no drug
 interactions with ARQ 197 (tivantinib) or cetuximab

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry and for
 the duration of study participation; should a woman become pregnant or suspect she is
 pregnant while she or her partner is participating in this study, she should inform
 her treating physician immediately; men treated or enrolled on this protocol must also
 agree to use adequate contraception prior to the study, for the duration of study
 participation, and 4 months after completion of ARQ 197 (tivantinib) administration

 -  Ability to understand and the willingness to sign a written informed consent document

 Exclusion Criteria:

 -  Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
 nitrosoureas or mitomycin C) prior to entering the study or those who have not
 recovered from adverse events due to agents administered more than 2 weeks earlier

 -  Nasopharyngeal tumors that show lymphoepithelioma histology

 -  Patients who have received more than 2 prior cytotoxic treatments in the palliative
 treatment setting are ineligible

 -  Patients who have received treatment with an EGFR or MET inhibitor in the palliative
 treatment setting are ineligible

 -  Patients with known, active brain metastases should be excluded from this clinical
 trial; patients with treated brain metastases stable for >= 12 weeks are eligible; use
 of corticosteroid (for patients with brain metastasis and other indications for
 corticosteroid use) is acceptable on a low maintenance or tapering dose schedule

 -  History of allergic reactions attributed to compounds of similar chemical or biologic
 composition to ARQ 197 (tivantinib) or cetuximab

 -  Concurrent life-threatening diseases: patients with diseases which with reasonable
 certainty do not limit life expectancy to 12 months or less are eligible; assessment
 of such concurrent illnesses should be by the principal investigator

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
 the mother is treated with ARQ 197 (tivantinib)

 -  Concurrent use of warfarin (therapeutic use) is allowed, but requires close monitoring
 of prothrombin time (PT)/international normalized ratio (INR)

 -  History of congestive heart failure defined as class II to IV per New York Heart
 Association (NYHA) classification; active coronary artery disease (CAD), clinically
 significant bradycardia or other uncontrolled, cardiac arrhythmia defined as >= grade
 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse
 Events (CTCAE), version 4.0, or uncontrolled hypertension; myocardial infarction
 occurring within 6 months prior to study entry (myocardial infarction occurring > 6
 months prior to study entry is permitted)

 -  Patients may not be receiving any other investigational agents