Ficlatuzumab w/wo Cetuximab in Patients w/Cetuximab-Resistant, Recurrent or Metastatic Head/Neck Squamous Cell Carcinoma

PRIMARY OBJECTIVES:

I. To assess the efficacy of ficlatuzumab, with or without concurrent cetuximab, in patients
with cetuximab-resistant, recurrent/metastatic head and neck squamous cell carcinoma (HNSCC)
as measured by progression-free survival (PFS).

SECONDARY OBJECTIVES:

I. To describe toxicity and patient-reported quality of life. II. To evaluate response rate
and overall survival in both treatment arms. III. To evaluate the relationship between
clinical outcomes (PFS, response rate [RR]) and candidate tumoral, genomic, peripheral, and
immune biomarkers, including: HGF/cMet, EGFR/EGFR, and EGFR/HER2 dimers; mutations in PIK3CA,
PTEN, and HRAS; peripheral serum biomarkers including VeriStrat, HGF, soluble HGF, and IL6;
peripheral lymphocyte populations; archived and baseline immune infiltrate.

OUTLINE: Patients are randomized into 1 of 2 arms.

ARM I: Patients receive ficlatuzumab intravenously (IV) over 30-60 minutes every 2 weeks in
the absence of disease progression or unaccepted toxicity. Courses repeat every 4 weeks in
the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 60 -120 minutes and ficlatuzumab IV over 30-60
minutes every 2 weeks in the absence of disease progression or unaccepted toxicity. Courses
repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Inclusion Criteria:

- Patients must have histologically confirmed HNSCC from any primary site; basaloid,
poorly differentiated, and undifferentiated carcinoma histologies will be accepted;
nasopharyngeal carcinoma, World Health Organization (WHO) type I and II (keratinizing,
non-Epstein-Barr virus [EBV] positive), will be included; paranasal sinus, lip and
external auditory canal sites will be included; squamous cell carcinoma of unknown
primary, clearly related to the head and neck, will be included

- Recurrent/metastatic disease, fulfilling at least one of the criteria defined below:

- Incurable disease as assessed by surgical or radiation oncology

- Metastatic (M1) disease

- Persistent or progressive disease following curative-intent radiation, and not a
candidate for surgical salvage due to incurability or morbidity; patients who
decline radical surgery are eligible

- For patients with oropharyngeal primary site or unknown primary site only: tumoral
human papillomavirus (HPV) status must be known, as established by the local site;
acceptable standards include p16 immunohistochemistry (where a tumor is classified as
p16-positive when showing diffuse nuclear and cytoplasmic staining in at least 70% of
tumor cells) and/or assessment of HPV deoxyribonucleic acid (DNA)

- Patients must be cetuximab-resistant by fulfilling at least one of the criteria
defined below:

- Disease persistence or recurrence within 6 months of completing definitive
radiotherapy for locally advanced disease; radiation must have included
concurrent cetuximab; induction chemotherapy, if given, may or may not have
included cetuximab

- Disease progression during, or within 6 months, of cetuximab treatment in the
recurrent/metastatic setting

- Prior cetuximab exposure may have occurred in any line of therapy (first line,
second line, etc.) and cetuximab is not required to be the most recent therapy
received

- Patients must be platinum-resistant or platinum-ineligible by fulfilling at least one
of the criteria defined below:

- Disease persistence or recurrence within 6 months of completing definitive
radiotherapy for locally advanced disease, where platinum chemotherapy was
administered as a component of induction and/or concurrent systemic treatment

- Disease progression during, or within 6 months, of treatment with platinum
chemotherapy (eg. carboplatin or cisplatin) in the recurrent/metastatic setting

- The patient is not an acceptable candidate for platinum chemotherapy due to
medical comorbidities, in the judgment of the local investigator

- Prior platinum exposure may have occurred in any line of therapy (first line,
second line, etc.) and is not required to be the most recent therapy received

- Prior exposure to immunotherapy, including anti-PD1/PDL1, anti-CTLA4, anti-tumor
necrosis factor receptor (TNFR) antibodies or other investigational immunotherapies,
is acceptable

- Eastern Cooperative Oncology Group performance status 0-1 at time of informed consent

- Patients must consent to a research biopsy of tumor tissue at baseline, for conduct of
correlative studies; archived biopsy material may only be substituted only if no
interval anti-cancer systemic therapy has been administered

- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria,
version 1.1

- Absolute neutrophil count (ANC) >= 1500/mm^3 (measured within 28 days of registration)

- Platelet count (PLT) >= 75,000/mm^3 (measured within 28 days of registration)

- Creatinine clearance >= 40 ml/min as determined by 24-hour collection or estimated by
the Cockcroft-Gault formula (measured within 28 days of registration)

- Serum bilirubin =< 1.5 times upper-limit of normal (ULN) (measured within 28 days of
registration)

- AST (aspartate aminotransferase) and ALT (alanine aminotransferase) =< 3 times ULN
(measured within 28 days of registration)

- No prior severe infusion reaction to cetuximab or a monoclonal antibody

- Written informed consent must be obtained from all patients prior to beginning
therapy; patients should have the ability to understand and the willingness to sign a
written informed consent document

- If a woman of childbearing potential, documentation of negative pregnancy within 14
days prior to registration; a negative pregnancy test must also be confirmed within 3
days of the first dose of ficlatuzumab; sexually active women of childbearing
potential must agree to use adequate contraceptive measures, while on study and for 30
days after the last dose of study drug; all fertile female subjects (and their
partners) must agree to use a highly effective method of contraception; effective
birth control includes (a) intrauterine device (IUD) plus one barrier method; or (b) 2
barrier methods; effective barrier methods are male or female condoms, diaphragms, and
spermicides (creams or gels that contain a chemical to kill sperm)

Exclusion Criteria:

- Nasopharyngeal primary site, if WHO type III (non-keratinizing and EBV-positive as
established at the local site)

- History of severe allergic or anaphylactic reactions or hypersensitivity to
recombinant proteins or excipients in the investigational agent

- Prior treatment with an hepatocyte growth factor (HGF)/cMet inhibitor such as
rilotumumab, crizotinib, MetMAb, or ARQ197

- Uncontrolled central nervous system (CNS) metastases, including leptomeningeal
metastases, are not allowed; subjects with previously treated brain metastases will be
allowed if the brain metastases have been stable without steroid treatment for at
least 2 weeks (radiotherapy or surgery)

- Failure to recover to grade 1 or baseline from all toxic effects of previous
chemotherapy, radiation therapy, biologic therapy, immunotherapy, and/or experimental
therapy, with the exception of: alopecia, grade =< 2 peripheral neuropathy, grade =< 2
cetuximab-related rash or other skin changes, hypomagnesemia (acceptable values
detailed below), hypokalemia (acceptable values detailed below), and the acceptable
hematologic values summarized above; a washout period of 2 weeks from prior cetuximab
is required; a washout period of 3 weeks from any prior cytotoxic chemotherapy,
targeted therapy, immunotherapy or investigational drug is required

- Significant pulmonary disease, including pulmonary hypertension or interstitial
pneumonitis

- Decreased serum albumin < 30 g/L (< 3 g/dL)

- Peripheral edema >= grade 2 per National Cancer Institute (NCI)-Common Terminology
Criteria for Adverse Events (CTCAE) version 4.0

- Significant electrolyte imbalance prior to enrollment (note that patients may be
supplemented to achieve acceptable electrolyte values):

- Hypomagnesemia < 1.2 mg/dL or 0.5 mmol/L

- Hypocalcemia < 8.0 mg/dL or 2.0 mmol/L

- Hypokalemia < 3.0 mmol/L

- Significant cardiovascular disease, including:

- Cardiac failure New York Heart Association (NYHA) class III or IV

- Myocardial infarction, severe or unstable angina within 6 months prior to study
day 1

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation)

- Cardiac arrhythmia requiring anti-arrhythmic medication(s); note that
beta-blockers, calcium channel blockers, and digoxin administered for the purpose
rate control of supraventricular tachycardia, including atrial fibrillation and
atrial flutter, are not classified as anti-arrhythmic medications for purposes of
trial eligibility

- Significant thrombotic or embolic events within 4 weeks prior to study day 1;
significant thrombotic or embolic events include but are not limited to stroke or
transient ischemic attack (TIA); catheter-related thrombosis is not a cause for
exclusion; diagnosis of deep vein thrombosis or pulmonary embolism is allowed if it
occurred > 4 weeks prior to study day 1 and the patient is asymptomatic and stable on
anti-coagulation therapy

- Any other medical condition (eg, alcohol abuse) or psychiatric condition that, in the
opinion of the investigator, might interfere with the subject?s participation in the
trial or interfere with the interpretation of trial results

- History of second malignancy within 2 years prior to study day 1 (except for excised
and cured non-melanoma skin cancer, carcinoma in situ of breast or cervix, superficial
bladder cancer, stage I differentiated thyroid cancer that is resected or observed, or
pT1a /pT1b prostate cancer comprising < 5% of resected tissue with normal prostate
specific antigen (PSA) since resection, or cT1a/cT1b prostate cancer treated with
brachytherapy or external beam radiation therapy with normal PSA since radiation)

- Major surgery within 6 weeks prior to study day 1 (subjects must have completely
recovered from any previous surgery prior to study day 1)

- Active infection requiring systemic antibiotics or antifungals within 7 days prior to
first dose of study drug; exception: tetracycline family antibiotics (tetracycline,
doxycycline, minocycline) administered for the management of cetuximab-related rash
may be continued per the investigator?s judgment

- 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;
Note: HIV testing is not required for entry into this protocol

- Women must not be pregnant or breastfeeding; pregnant women are excluded from this
study