Erlotinib, Docetaxel, and Radiation Therapy in Stage III or Stage IV Squamous Cell Carcinoma of the Head and Neck

A Phase II Study of the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Erlotinib, in Combination With Docetaxel and Radiation in Locally Advanced Squamous Cell Cancer of the Head and Neck

RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving erlotinib together with docetaxel and radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well erlotinib given together with docetaxel and radiation therapy works in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.

Study Overview

• Status: Completed
• Conditions: Head and Neck Cancer
• Intervention / Treatment: Drug: docetaxel; Drug: erlotinib hydrochloride; Genetic: fluorescence in situ hybridization; Genetic: polymerase chain reaction; Other: immunoenzyme technique; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: therapeutic conventional surgery; Radiation: intensity-modulated radiation therapy; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

Primary

• Determine the time to progression in patients with locally advanced squamous cell carcinoma of the head and neck treated with erlotinib hydrochloride in combination with docetaxel and radiotherapy.

Secondary

• Determine objective response rate, locoregional control rate, duration of response, patterns of failure, and overall survival in patients treated with this regimen.
• Determine the toxicities of this regimen in these patients.
• Determine the dose and effect of this treatment on biologic correlates in tumor tissue and/or surrounding mucosa.

OUTLINE: This is a multicenter study.

Patients receive oral erlotinib hydrochloride once daily for up to 2 years in the absence of disease progression or unacceptable toxicity. Beginning on week 3, patients receive docetaxel IV over 1 hour once a week and radiotherapy (may be intensity-modulated) once daily for 8 weeks in the absence of disease progression or unacceptable toxicity.

At 6-8 weeks after completion of chemoradiotherapy, patients with N2 or greater cervical lymph node involvement at baseline or with residual disease may undergo surgery. Patients with persistent disease during study therapy undergo salvage surgery 6-12 weeks after completion of chemoradiotherapy.

Patients undergo blood sample, tissue biopsy, mucosal scraping, and saliva collection at baseline and periodically during study. Samples are analyzed for markers of angiogenic activity (VEGF, sVEGFR-2, sKIT, ICAM, and PDGF), pharmacokinetic studies, gene expression profile, and human papilloma virus DNA by enzyme linked immunosorbent assay (ELISA), immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR.

After completion of study therapy, patients will be evaluated every 4-8 weeks for 1 year, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 2 years, and then once a year thereafter.

• Study Type: Interventional
• Enrollment (Actual): 43
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106-5065
      • University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed locally advanced squamous cell carcinoma of the head and neck

  • Stage III or IV disease

    • No distant metastatic disease
• Measurable disease (according to RECIST)
• No salivary gland and paranasal sinus squamous cell carcinoma

• No known brain metastases or direct cerebral invasion by tumor

  • Intracranial extension (without cerebral involvement) may be allowed

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Life expectancy > 12 weeks
• ANC ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥10 g/dL
• Total bilirubin normal

• Alkaline phosphatase AND AST and ALT meeting the following criteria:

  • Alkaline phosphatase normal AND AST and ALT ≤ 5 times upper limit of normal (ULN)
  • Alkaline phosphatase ≤ 2.5 times ULN AND AST and ALT ≤ 2.5 times ULN
  • Alkaline phosphatase ≤ 5 times ULN AND AST and ALT normal
• Creatinine normal OR creatinine clearance ≥ 60 mL/min

• No clinically significant heart disease including any of the following:

  • NYHA class III or IV heart disease
  • Significant arrhythmias requiring medication
  • Symptomatic coronary artery disease
  • Myocardial infarction within the previous six months
  • Second- or third-degree heart block or bundle-branch block
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after completion of study therapy
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib hydrochloride or docetaxel, including other drugs formulated with polysorbate 80
• No pre-existing peripheral neuropathy ≥ grade 2

• No uncontrolled concurrent illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness/social situations that would preclude compliance with study requirements
• No HIV positivity

• No other prior malignancy except for any of the following:

  • Squamous cell or basal cell carcinoma of the skin
  • Carcinoma in situ of the cervix
  • Cancer that was treated more than 5 years ago and the patient has remained disease-free
• Not poorly compliant

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiotherapy, or investigational antitumor drug
• No other concurrent investigational agents

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: oral erlotinib hydrochloride

Drug: docetaxel; Beginning on week 3, patients receive docetaxel IV over 1 hour once a week; Drug: erlotinib hydrochloride; oral erlotinib hydrochloride once daily for up to 2 years in the absence of disease progression or unacceptable toxicity; Genetic: fluorescence in situ hybridization; Patients undergo blood sample, tissue biopsy, mucosal scraping, and saliva collection at baseline and periodically during study. Samples are analyzed for markers of angiogenic activity (VEGF, sVEGFR-2, sKIT, ICAM, and PDGF), pharmacokinetic studies, gene expression profile, and human papilloma virus DNA by enzyme linked immunosorbent assay (ELISA), immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR.; Genetic: polymerase chain reaction; Patients undergo blood sample, tissue biopsy, mucosal scraping, and saliva collection at baseline and periodically during study. Samples are analyzed for markers of angiogenic activity (VEGF, sVEGFR-2, sKIT, ICAM, and PDGF), pharmacokinetic studies, gene expression profile, and human papilloma virus DNA by enzyme linked immunosorbent assay (ELISA), immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR.; Other: immunoenzyme technique; Patients undergo blood sample, tissue biopsy, mucosal scraping, and saliva collection at baseline and periodically during study. Samples are analyzed for markers of angiogenic activity (VEGF, sVEGFR-2, sKIT, ICAM, and PDGF), pharmacokinetic studies, gene expression profile, and human papilloma virus DNA by enzyme linked immunosorbent assay (ELISA), immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR.; Other: immunohistochemistry staining method; Patients undergo blood sample, tissue biopsy, mucosal scraping, and saliva collection at baseline and periodically during study. Samples are analyzed for markers of angiogenic activity (VEGF, sVEGFR-2, sKIT, ICAM, and PDGF), pharmacokinetic studies, gene expression profile, and human papilloma virus DNA by enzyme linked immunosorbent assay (ELISA), immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR.; Other: laboratory biomarker analysis; Patients undergo blood sample, tissue biopsy, mucosal scraping, and saliva collection at baseline and periodically during study. Samples are analyzed for markers of angiogenic activity (VEGF, sVEGFR-2, sKIT, ICAM, and PDGF), pharmacokinetic studies, gene expression profile, and human papilloma virus DNA by enzyme linked immunosorbent assay (ELISA), immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR.; Other: pharmacological study; Patients undergo blood sample, tissue biopsy, mucosal scraping, and saliva collection at baseline and periodically during study. Samples are analyzed for markers of angiogenic activity (VEGF, sVEGFR-2, sKIT, ICAM, and PDGF), pharmacokinetic studies, gene expression profile, and human papilloma virus DNA by enzyme linked immunosorbent assay (ELISA), immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR.; Procedure: therapeutic conventional surgery; At 6-8 weeks after completion of chemoradiotherapy, patients with N2 or greater cervical lymph node involvement at baseline or with residual disease may undergo surgery.Patients with persistent disease during study therapy undergo salvage surgery 6-12 weeks after completion of chemoradiotherapy.; Radiation: intensity-modulated radiation therapy; radiotherapy (may be intensity-modulated) once daily for 8 weeks in the absence of disease progression or unacceptable toxicity.; Radiation: radiation therapy; radiotherapy (may be intensity-modulated) once daily for 8 weeks in the absence of disease progression or unacceptable toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Participants With Disease-Free Survival (DFS) at 3 Years	Percent of participants with Disease-Free survival (DFS) at 3 years. Assessed from date of treatment to date of death or date of disease progression, and to date of last follow-up for those still alive and progression free. Disease-free Survival percentages were calculated using Kaplan-Meier estimates.	3 yrs after treatment
Time to Progression (TTP)	Time from start of treatment to first documented occurrence of progressive disease (PD). PD defined as at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.	3 yrs after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate (Complete Response, Partial Response, Stable Disease, and Disease Progression)	Response rate according to response criteria, which defines the following: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions	3 yrs after treatment
Overall Survival (OS)	Percent of participants alive at follow-up time. Overall survival time is evaluated from the date of treatment to date of death, and to date of last follow-up for those still alive.	3 years
Number of Participants With Acute Grade III/IV Treatment-related Toxicities	Number of participants with acute grade III/IV treatment-related toxicities	evaluated every 2 weeks, up to 3 years
Percent of Participants With Local Failure-free Survival	Participants with Local absence of relapse or recurrence or progression within the prescribed radiation field.	At 3 years
Percent of Participants With Regional Failure-free Survival	Participants with the regional absence of relapse or recurrence or progression within the prescribed radiation field. Failure-free Survival percentages were calculated using Kaplan-Meier estimates.	At 3 years
Percent of Participants With Locoregional Failure-free Survival	Participants with the locoregional absence of relapse or recurrence or progression within the prescribed radiation field. Locoregional failure-free survival percentages were calculated using Kaplan-Meier estimates.	At 3 years
Percent of Participants With Distant Metastasis-free Survival	Percent of participants with distant metastasis-free survival	At 3 years

Other Outcome Measures

Outcome Measure	Time Frame
Predictive Values of EGFR/TGF-α, VEGF	collection at baseline and periodically during study.

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Min Yao, MD, University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2007
• Primary Completion (Actual): November 13, 2015
• Study Completion (Actual): November 13, 2015

Study Registration Dates

• First Submitted: July 19, 2008
• First Submitted That Met QC Criteria: July 19, 2008
• First Posted (Estimated): July 22, 2008

Study Record Updates

• Last Update Posted (Actual): August 22, 2024
• Last Update Submitted That Met QC Criteria: August 19, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: metastatic squamous neck cancer with occult primary squamous cell carcinoma; stage III squamous cell carcinoma of the lip and oral cavity; stage III verrucous carcinoma of the oral cavity; stage IV squamous cell carcinoma of the lip and oral cavity; stage IV verrucous carcinoma of the oral cavity; stage III squamous cell carcinoma of the oropharynx; stage IV squamous cell carcinoma of the oropharynx; stage III squamous cell carcinoma of the nasopharynx; stage IV squamous cell carcinoma of the nasopharynx; stage III squamous cell carcinoma of the hypopharynx; stage IV squamous cell carcinoma of the hypopharynx; stage III squamous cell carcinoma of the larynx; stage III verrucous carcinoma of the larynx; stage IV squamous cell carcinoma of the larynx; stage IV verrucous carcinoma of the larynx
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Squamous Cell; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Docetaxel; Erlotinib Hydrochloride
• Other Study ID Numbers: CASE5307 (Case Comprehensive Cancer Center); P30CA043703 (U.S. NIH Grant/Contract); CASE-IRB-05-02-12 (Other Identifier: University Hospitals IRB)