This randomized phase II trial studies how well ficlatuzumab with or without cetuximab work
in treating patients with head and neck squamous cell carcinoma that has come back or spread
to other places in the body and resistant to cetuximab treatment. Monoclonal antibodies, such
as ficlatuzumab and cetuximab, may block growth signals that lets a tumor cell survive and
reproduce, and helps the immune system recognize and fight head and 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, except
nasopharyngeal if WHO Type III (non-keratinizing and EBV-positive).
Eligible histologies include:
- Basaloid, poorly differentiated, and undifferentiated carcinoma histologies.
- Nasopharyngeal carcinoma, WHO Type I and II (keratinizing, non-EBV positive).
- Paranasal sinus, lip and external auditory canal sites.
- Squamous cell carcinoma of unknown primary, clearly related to the head and neck.
Note: Documentation of primary site diagnosis must be submitted with the registration
request.
- Patients must have recurrent and/or 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. Note: Patients who
decline radical surgery are eligible.
- For patients with oropharyngeal primary site or unknown primary site only: Patients
must have known tumoral HPV status (p16). (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 DNA.) Note: For these subjects, documentation of p16 status must be submitted with
the registration packet.
- Patients must be cetuximab-resistant by fulfilling at least one of the two criteria
defined below:
- Disease persistence or recurrence within 6 months of completing definitive
radiotherapy with concurrent cetuximab for locally advanced disease. Induction
chemotherapy, if given, may or may not have included cetuximab.
- Disease progression during, or within 6 months, of cetuximab treatment in the
recurrent and/or metastatic setting.
Note: Prior cetuximab 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.
- Patients must be platinum-resistant or platinum-ineligible by fulfilling at least one
of the three 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 (e.g., carboplatin or cisplatin) in the recurrent and/or metastatic
setting.
- The patient is not an acceptable candidate for platinum chemotherapy due to medical
comorbidities, in the judgment of the local investigator.
Note: 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.
- Patients must have prior exposure to an anti-PD1 or anti-PDL1 mAb, if eligible for
immunotherapy in the judgment of the local investigator.
Note: Prior exposure to investigational immunotherapies, including anti-CTLA4, anti-OX40,
anti-CD40, anti-CD27, anti-TNFR antibodies or other investigational immunotherapies, is
acceptable.
- Patients must have Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1 at
time of informed consent (see Appendix B).
- Patients must be age ≥ 18 years.
- Patients must consent to a research biopsy of tumor tissue at baseline, for conduct of
correlative studies. In cases where a fresh biopsy is not feasible (i.e., if an
accessible tumor site cannot be biopsied with acceptable clinical risk), archival
tissue may be submitted instead, after discussion with and approval by the
Sponsor-Investigator.
- Patients must have measurable disease per RECIST criteria, version 1.1 (see section 6)
per scan within 28 days prior to registration.
- Patients must have adequate electrolytes, liver, renal, and hematology function as
defined below within 28 days of registration:
- Absolute neutrophil count (ANC) ≥ 1500/mm3
- Platelet count (PLT) ≥ 75,000/mm3
- Creatinine clearance ≥ 30 mL/min per estimated by the Cockraft-Gault formula:
- Calculated Creatinine Clearance = [(140-age) X (actual body weight in kg) X (0.85 if
female)]/(72 X serum creatinine)
* Total bilirubin ≤ 1.5 times upper-limit of normal (ULN)
- AST (aspartate aminotransferase) ≤ 3 times ULN
- ALT (alanine aminotransferase) ≤ 3 times ULN
- Magnesium ≥ 1.2 mg/dL or 0.5 mmol/L
- Corrected Calcium ≥ 8.0 mg/dL or 2.0 mmol/L
- Potassium ≥ 3.0 mmol/L (Note: Patients may be supplemented to achieve acceptable
electrolyte values.)
- Serum albumin ≥ 25 g/L (≥ 2.5 g/dL)
- Patients must sign written informed consent prior to beginning study screening
procedures. Patients must have the ability to understand and the willingness to sign a
written informed consent document.
- Women of child-bearing potential (WOCBP) must agree to have a pregnancy test within 14
days prior to registration and a repeated test within 3 days of the first dose of
ficlatuzumab.
- Patients must agree to use highly effective contraceptive measures while on study and
for 60 days after the last dose of study drug. This includes: Men of reproductive
potential AND women of childbearing potential.
- 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 HGF/cMet inhibitor such as rilotumumab, crizotinib, MetMAb, or
ARQ197.
- Uncontrolled central nervous system (CNS) metastases, including leptomeningeal
metastases, are not allowed.
Note: 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 in the exclusion criteria below),
- Hypokalemia (acceptable values detailed in the exclusion criteria below), and
- The acceptable ANC and PLT inclusion criteria values above.
- Treatment with cetuximab 2 weeks prior to the first dose of study drug. A washout
period of 2 weeks from prior cetuximab is required if applicable.
- Treatment with cytotoxic chemotherapy, targeted therapy, immunotherapy or
investigational drug 3 weeks prior to the first dose of study drug. A washout period
of 3 weeks from any prior cytotoxic chemotherapy, targeted therapy, immunotherapy or
investigational drug is required, if applicable.
- Significant underlying pulmonary disease, including pulmonary hypertension or
interstitial pneumonitis.
- Peripheral edema ≥ Grade 2 per NCI-CTCAE version 4.0.
- Significant cardiovascular disease, including:
- Cardiac failure New York Heart Association (NYHA) class III or IV.
- Myocardial infarction within 6 months prior to registration.
- Severe or unstable angina within 6 months prior to registration.
- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation).
- Cardiac arrhythmia requiring anti-arrhythmic medication(s). (Beta-blockers, calcium
channel blockers, and digoxin administered for the purpose of 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 28 days prior to registration.
(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 > 28 days prior to registration and the patient is asymptomatic and stable on
anti-coagulation therapy.)
- Any other medical condition (e.g., alcohol abuse) or psychiatric condition that, in
the opinion of the local 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 registration except:
- 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,
- 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.
- Not completely recovered from any previous surgery. Note: Complete recovery is in the
opinion of the treating investigator. Consult the Sponsor-Investigator, if needed.
- Active systemic infection requiring systemic antibiotics or antifungals within 7 days
prior to first dose of study drug, except tetracycline family antibiotics
(tetracycline, doxycycline, minocycline) administered for the management of
cetuximab-related rash may be continued per the Investigator's judgment.
Note: Active topical infections (for example oral thrush) do not exclude a subject even if
treated with systemic antibiotics or systemic antifungals.
- History of severe infusion reaction to cetuximab or a monoclonal antibody.
- Known to be HIV positive. Note: HIV testing is not required for entry into this
protocol.
- Women who are pregnant or breastfeeding. (A negative urine pregnancy test must be
confirmed within 14 days of registration and repeated within 3 days of the first dose
of study drug.)
