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

December 28, 2017 updated by: National Cancer Institute (NCI)

Phase II Randomized Trial of the Combination of Cetuximab and Sorafenib or Single Agent Cetuximab in Patients With Refractory, Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Monoclonal antibodies, such as cetuximab, 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. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether cetuximab is more effective when given alone or together with sorafenib tosylate in treating patients with head and neck cancer. This randomized phase II trial is studying cetuximab to see how well it works when given together with or without sorafenib tosylate in treating patients with refractory, recurrent, and/or metastatic head and neck cancer.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

55

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Tampa, Florida, United States, 33612
        • H. Lee Moffitt Cancer Center and Research Institute
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University/Winship Cancer Institute
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins University/Sidney Kimmel Cancer Center
      • Bethesda, Maryland, United States, 20814
        • Suburban Hospital
    • Montana
      • Billings, Montana, United States, 59107-7000
        • Billings Clinic
    • New York
      • Bronx, New York, United States, 10467-2490
        • Montefiore Medical Center
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt-Ingram Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Arm I (cetuximab and placebo)
Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral placebo twice daily on days 1-21.
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Names:
  • quality of life assessment
Other: placebo
Given orally
Other Names:
  • PLCB
Biological: cetuximab
Given IV
Other Names:
  • C225
  • IMC-C225
  • C225 monoclonal antibody
  • MOAB C225
  • monoclonal antibody C225
Experimental: Arm II (cetuximab and sorafenib tosylate)
Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 and oral sorafenib tosylate twice daily on days 1-21.
Other: laboratory biomarker analysis
Correlative studies
Procedure: quality-of-life assessment
Ancillary studies
Other Names:
  • quality of life assessment
Drug: sorafenib tosylate
Given orally
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Biological: cetuximab
Given IV
Other Names:
  • C225
  • IMC-C225
  • C225 monoclonal antibody
  • MOAB C225
  • monoclonal antibody C225

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Progression Free Survival (PFS)
Time Frame: 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.
On-study date to lesser of date of progression or date of death from any cause (assessed up to 3 years)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Best Response
Time Frame: 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.
On-treatment date to date of disease progression (assessed up to 3 years)
Overall Survival (OS)
Time Frame: 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)
On-study date to date of death from any cause (assessed up to 3 years)
Number of Participants With Each Worst-Grade Toxicity
Time Frame: 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
On-study date to 30 days following final dose of study drug
Gene Expression Levels
Time Frame: 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.
Pre-therapy
Overall Survival Associated With Immunomodulatory Cytokines
Time Frame: 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.
Pre-therapy, up to about 42 months (follow-up for overall survival)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of Life
Time Frame: up to 3 years
Quality of Life Survey results.
up to 3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2009

Primary Completion (Actual)

January 1, 2013

Study Completion (Actual)

January 1, 2014

Study Registration Dates

First Submitted

July 14, 2009

First Submitted That Met QC Criteria

July 14, 2009

First Posted (Estimate)

July 15, 2009

Study Record Updates

Last Update Posted (Actual)

January 23, 2018

Last Update Submitted That Met QC Criteria

December 28, 2017

Last Verified

December 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2012-02847 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • MCC-15780 (Other Identifier: H. Lee Moffitt Cancer Center and Research Institute)
  • 8070 (CTEP)
  • P30CA076292 (U.S. NIH Grant/Contract)
  • N01CM00100 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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