Phase II Randomized Trial of the Combination of Cetuximab and Sorafenib or Single Agent Cetuximab

PRIMARY OBJECTIVES:

I. Compare the progression free survival (PFS) of the combination of cetuximab and sorafenib to that of cetuximab alone in patients with recurrent, refractory or metastatic squamous cell carcinoma of the head and neck (SCCHN).

SECONDARY OBJECTIVES:

I. To evaluate the response rate, overall survival (OS) and toxicity of the combination of cetuximab and sorafenib and of cetuximab alone.

II. To evaluate the presence of EGFRvIII mutation, increased EGFR gene copy number and activated EGFR gene expression signature, and correlate with clinical parameters (RR, OS and PFS) in the cetuximab alone and cetuximab/sorafenib arms.

III. To evaluate whether VEGF receptor family and their ligand expression can predict response to cetuximab/sorafenib.

IV. To determine the proteomic profiles in serum and tumors that can predict the response and survival upon the treatment with cetuximab or cetuximab/sorafenib.

V. To evaluate the effect of therapy on both general and head and neck specific functionality, symptom burden and QOL.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral placebo twice daily on days 1-21. (oral placebo closed as of 02/18/2010).

ARM II: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral sorafenib tosylate twice daily on days 1-21.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Paraffin embedded tissue samples are collected at baseline for pharmacogenomic studies and blood samples are collected at baseline and for the first 3 courses for research purposes. Quality of life and symptom burden are assessed by Vanderbilt Head and Neck Symptom Survey, FACT-HN, and Fatigue and Pain Inventory questionnaires at baseline, at day 43, and at 3 and 6 months.

After completion of study treatment, patients are followed periodically for 3 years.

• cetuximab (Biological), also known as C225, C225 monoclonal antibody, IMC-C225, MOAB C225, monoclonal antibody C225: Given IV
• placebo (Other), also known as PLCB: Given orally
• sorafenib tosylate (Drug), also known as BAY 43-9006, BAY 43-9006 Tosylate Salt, BAY 54-9085, Nexavar, SFN: Given orally
• laboratory biomarker analysis (Other): Correlative studies
• quality-of-life assessment (Procedure), also known as quality of life assessment: Ancillary studies

Primary outcomes

• Progression Free Survival (PFS) [On-study date to lesser of date of progression or date of death from any cause (assessed up to 3 years)]: Estimated probable duration of life without disease progression, from on-study date to earlier of progression date or date of death from any cause, using the Kaplan-Meier method with censoring (see analysis population description for additional details). Disease progression is defined under Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as >=20% increase in sum of longest diameters of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions.

Secondary outcomes

• Best Response [On-treatment date to date of disease progression (assessed up to 3 years)]: Number of patients in each response category, per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, summarized as follows for target lesion criteria (see RECIST v1.1 for additional details): complete response (CR),disappearance of target lesions; partial response (PR), >=30% decrease in sum of longest diameter of target lesions; progressive disease (PD), >=20% increase in sum of longest diameter (LD) of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or SD. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>SD>PD.
• Overall Survival (OS) [On-study date to date of death from any cause (assessed up to 3 years)]: Estimated probable duration of life from on-study date to date of death from any cause, using the Kaplan-Meier method with censoring (see analysis population description for additional details)
• Number of Participants With Each Worst-Grade Toxicity [On-study date to 30 days following final dose of study drug]: Count of patients according to the worst-grade toxicity experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; grade 5, death
• Gene Expression Levels [Pre-therapy]: Formalin-fixed, paraffin-embedded (FFPE) tumors were collected. The FFPE tumors were to be evaluated for p16 expression using immunohistochemistry staining with antibody. Gene Expression Levels (positive when >70% cells stained, otherwise negative) were to be described using frequencies.
• Overall Survival Associated With Immunomodulatory Cytokines [Pre-therapy, up to about 42 months (follow-up for overall survival)]: Twelve immunomodulatory cytokines were selected based on previous a feasibility study and detected using multiplex Luminex bead assays from patient's plasma. One cytokines, HGF, was eliminated due to extremely low expression. Three representative cytokines, TGF-beta 1, IL-8 and VEGF were to be evaluated for association with survival due to clustering.

Other outcomes

• Quality of Life [up to 3 years]: Quality of Life Survey results.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with recurrent, refractory or metastatic squamous cell carcinoma of oral cavity, oropharynx and larynx, hypopharynx or paranasal sinus, head and neck unknown primary or nasopharyngeal carcinoma WHO type 1; patients with recurrent, refractory or metastatic squamous cell carcinoma of oral cavity, oropharynx and larynx, hypopharynx or paranasal sinus, head and neck unknown primary or nasopharyngeal carcinoma WHO type 1; patients may have had up to 1 prior palliative chemotherapy for recurrent or metastatic disease; please note that chemotherapy given as part of a regimen for curative intent for recurrent disease does not count as "prior chemotherapy;" patients must not presently be candidates for curative therapy
* ECOG performance status 0, 1 or 2
* Hemoglobin >= 9.0/dl
* Absolute-neutrophil count (ANC) >= 1500/mm\^3
* Platelet count >= 100,000/mm\^3
* Total bilirubin =< 1.5 x ULN
* ALT and AST =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement)
* INR < 1.5 or a PT and PTT within normal limits
* Creatinine =< 1.5 x ULN
* If primary therapy was given for curative intent, at least 4 weeks must have elapsed after completion of primary therapy prior to enrollment on this clinical trial; however, toxicities from prior treatment must have resolved to grade 1 or less
* Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of the treatment; women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation (i.e, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study and for a minimum of 3 months following the last dose of chemotherapy; male subject agrees to use an acceptable method for contraception for the duration of the study and for a minimum of 3 months following the last dose of chemotherapy
* Patients must have a measurable disease defined by RECIST criteria
* Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care; patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial

Exclusion Criteria:

* Prior treatment with sorafenib or cetuximab
* Patients with active clinically significant infection or with a fever >= 38.5º C within 3 days of the first scheduled day of protocol treatment
* History of prior malignancy within the past 3 years except for curatively treated basal cell carcinoma and squamous cell carcinoma of the skin, CIN or localized prostate cancer with a current PSA < 1.0 mg/dL on 2 successive evaluations at least 3 months apart, with the most recent evaluation within 4 weeks of study entry
* Patients with known hypersensitivity to sorafenib or cetuximab
* Prior severe infusion reaction to a monoclonal antibody
* History of hand-foot syndrome
* Pregnant or lactating; sexually active women of childbearing potential must use an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized
* Known untreated brain metastasis; patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis or progression of brain metastasis; patients with treated brain metastasis are eligible for study as long as no evidence of progression of CNS disease; hemorrhagic brain metastases are not allowed on study
* Uncontrolled comorbid illness
* Patients with HIV who are taking antiretroviral mediations will be excluded because of the potential interactions of anti-retroviral medications with these agent; however, given the potential immune modulating effects of sorafenib, investigators should still be very cautious about placing HIV positive patients on this trial as the effects of these medications on the HIV virus itself are not know
* History of allogeneic transplant
* Patient has received other investigational drugs within 28 days before enrollment
* Cardiac disease: congestive heart failure > class II NYHA; patients must not have unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months; significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension (defined as defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management), uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction will also be excluded from study; cardiac ventricular arrhythmias requiring anti-arrhythmic therapy will also be excluded from study
* Thrombotic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months
* Pulmonary hemorrhage/bleeding event > CTCAE grade 2 within 4 weeks of first dose of study drug
* Any other hemorrhage/bleeding event > CTCAE grade 3 within 4 weeks of first dose of study drug
* Tumor that invades the carotid artery as shown unequivocally by imaging studies
* Serious non-healing wound, ulcer, or bone fracture
* Evidence or history of bleeding diathesis or coagulopathy
* Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug
* Use of St. John's Wort or rifampin (rifampicin)
* Use of the following medications will not be allowed within 4 weeks prior to enrollment on the study and during the study: ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin, phenobarbital; products containing grapefruit juice will not be allowed while on study
* Known or suspected allergy to sorafenib or any agent given in the course of this trial
* Any malabsorption problem
* Known HIV positive patients will be excluded from trial due to the potential immune modulation that these agents may cause

Participant flow

Outcome results

• Progression Free Survival (PFS) (Primary), Median, months: Arm A - Cetuximab 3 (1.9 to 5.0); Arm B - Cetuximab and Sorafenib Tosylate 3.2 (1.8 to 4.2)
• Best Response (Secondary), Number, participants: Arm A - Cetuximab 0; Arm B - Cetuximab and Sorafenib Tosylate 0
• Overall Survival (OS) (Secondary), Median, months: Arm A - Cetuximab 9 (5.2 to 12.9); Arm B - Cetuximab and Sorafenib Tosylate 5.7 (4.2 to 10.8)
• Number of Participants With Each Worst-Grade Toxicity (Secondary), Number, participants: Arm A - Cetuximab 6; Arm B - Cetuximab and Sorafenib Tosylate 7
• Gene Expression Levels (Secondary)
• Overall Survival Associated With Immunomodulatory Cytokines (Secondary)
• Quality of Life (Other pre specified)

Adverse events

Time frame: 2 years, 4 months

Serious adverse events by term

Other adverse events by term

75 more terms not shown.

Limitations and caveats: Accrual ended early based on planned interim analysis, but the study was completed with existing participants.

• Results publication: Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol. 2014 Nov;25(11):2101-2115. doi: 10.1093/annonc/mdu265. Epub 2014 Jul 23. PMID 25057165

• Jill Gilbert, Principal investigator, H. Lee Moffitt Cancer Center and Research Institute

NIH grants: P30CA076292, N01CM00100