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Phase II Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma With Evaluation of Neoadjuvant Biomarker Modulation With TARCEVA vs. TARCEVA Plus Sulindac

Phase 2
18 Years
Open (Enrolling)
Head and Neck Squamous Cell Carcinoma

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Trial Information

Phase II Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma With Evaluation of Neoadjuvant Biomarker Modulation With TARCEVA vs. TARCEVA Plus Sulindac

Head and neck squamous cell carcinoma (HNSCC) constitutes 3 percent of all malignancies and
is the sixth most common malignancy worldwide. There will be an estimated 38,000 new cases
and 11,000 deaths in the United States in 2004 and approximately 500,000 cases worldwide
yearly [1]. Squamous cell carcinoma accounts for at least 95 percent of all head and neck
cancers. Surgical treatment remains the standard of therapy for patients with resectable
HNSCC. For patients with high risk of local or distant relapse, radiation therapy (RT)
alone, or in combination with chemotherapy, is given after surgery to improve loco-regional
control and overall survival.

Neoadjuvant chemotherapy for patients with respectable HNSCC remains an experimental option
for these patients. A two-week delay in definitive surgical resection in patients with
operable HNSCC is not thought to impact the clinical outcome of these patients and in many
cases may be needed to complete all of the preoperative work-up. As a result, a study design
involving a two-week preoperative course of therapy in patients with operable HNSCC should
not be a concern.

EGFR as a therapeutic target in HNSCC

Epidermal growth factor receptor (EGFR) is a 170-Kda transmembrane protein that is thought
to be important in the proliferation and survival of cancer cells [2]. Overexpression of
EGFR has been found in several malignancies, including head and neck, lung, breast,
prostate, bladder, and pancreatic cancer [3-7]. In HNSCC, EGFR and its ligand TGF are
overexpressed in 80-90% of tumors compared to normal mucosa; [8] the coexpression of
receptor and ligand implicates an autocrine regulatory pathway in HNSCC carcinogenesis. The
clinical relevance of EGFR overexpression as an independent prognostic factor in HNSCC has
been well demonstrated. High tumor EGFR levels are correlated with advanced stage,[9]
increased tumor size, [9] decreased survival,[10-13] increased recurrence,[10] and decreased
sensitivity to radiation treatment [14]. A recent study suggests that high serum EGFR levels
may even correlate with higher head and neck tumor grade [15]. The overexpression of EGFR
and ligand in partially and fully transformed HNSCC tissue, its correlation with poor
clinical outcome, and the aberrant function of the EGFR network in HNSCC provide compelling
evidence of a relationship between EGFR and the development and progression of HNSCC, and
suggest a role for EGFR as a target for cancer therapy.

EGFR has been targeted at the extracellular domain by blocking ligand binding, at the
intracellular domain by inhibiting tyrosine kinase activity, and at the genetic level by
targeting production of the receptor itself. EGFR-specific monoclonal antibodies interfere
with ligand binding, while conjugation of an EGFR ligand or antibody to a bacterially
derived toxin enables the delivery of a cytotoxic agent to the cell surface. Many of the
EGFR-targeting agents are undergoing clinical evaluation in HNSCC. In general, clinical
responses in HNSCC patients with advanced disease have only been observed when these agents
have been combined with cytotoxic chemotherapy or radiation therapy. Clinical trials using
EGFR inhibitors as adjuvant therapy for HNSCC are currently underway.

Inclusion Criteria:

- Histologically or cytologically confirmed, previously untreated HNSCC.

- Clinical stage II, III or IVA disease without distant metastasis, as defined by the
American Joint Committee on Cancer Staging System, Sixth edition (See Appendix I).

- Primary tumors of the oral cavity, oropharynx, hypopharynx, or larynx will be
included. Primary tumors of the sinuses, paranasal sinuses, or nasopharynx, or
unknown primary tumors are NOT allowed.

- Macroscopic complete resection of the primary tumor must be planned.

- Patients will be willing to receive postoperative therapy with platinum and radiation
if qualified based on criteria listed in treatment plan.

- Age 18 years.

- ECOG performance status 0-1 (See Appendix II).

- Adequate hematologic, renal and hepatic function, as defined by:

- Absolute neutrophil count (ANC) greater than 1,500/ul, platelets greater than

- Creatinine less than 1.5 x institutional upper limit of normal (ULN).

- Bilirubin less than 1.5 x ULN, AST or ALT 2.5 x ULN.

- Have signed written informed consent.

Exclusion Criteria:

- Subjects who fail to meet the above criteria.

- Pregnancy or breastfeeding. Women of childbearing potential (WOCBP) must practice
acceptable methods of birth control to prevent pregnancy.

- Subjects with a ECOG performance status of 2 or worse.

- Evidence of distant metastasis.

- Any other malignancy active within 5 years except for non-melanoma skin cancer or
carcinoma in situ of the cervix, DCIS or LCIS of the breast.

- Prior history of HNSCC.

- Prior therapy targeting the EGFR pathway.

- Known severe hypersensitivity to sulindac or other non-steroidal anti-inflammatory
drugs (NSAIDs), including aspirin.

- Any unresolved chronic toxicity greater than grade 2 from previous anticancer therapy
(except alopecia), according to Common Terminology Criteria for Adverse Events v3.0

- Incomplete healing from previous major surgery.

- Acute hepatitis, known HIV, or active uncontrolled infection.

- History of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable
angina, myocardial infarction within prior 6 months, untreated known coronary artery
disease, uncontrolled congestive heart failure, and cardiomyopathy with decreased
ejection fraction.

- Any preexisting active interstitial lung disease (patients with chronic stable
radiographic changes who are asymptomatic are NOT excluded).

- Treatment with anticoagulants, except when used to maintain the patency of a central
venous line.

- Uncontrolled peptic or gastric ulcer disease, or gastrointestinal bleeding within
prior 6 months.

- Active alcohol abuse or other illness that carries a likelihood of inability to
comply with study treatment and follow-up.

- Treatment with a non-approved or investigational drug within 30 days prior to Day 1
of study treatment.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Outcome Measure:

Phase II Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma with Evaluation of Neoadjuvant Biomarker Modulation with TARCEVA vs. TARCEVA Plus Sulindac

Outcome Description:

Primary objective centered around concept of tumor biomarkers which may be modulated by EGFR & Cox-2 inhibitors & may serve as future therapeutic targets for therapy. Patients on this trial to be randomly assigned to 1 of 3 arms in the 2 week pre-operative period. A panel of biomarkers will be obtained by biopsy prior to pre-operative therapy and again at surgery. Biomarkers will be examined for modulation in the 2-week pre-operative period, for group differences, for treatment effects and for further understanding of protein signaling pathways.

Outcome Time Frame:

10 years

Safety Issue:


Principal Investigator

Jennifer Grandis, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh


United States: Institutional Review Board

Study ID:




Start Date:

November 2005

Completion Date:

January 2014

Related Keywords:

  • Head and Neck Squamous Cell Carcinoma
  • Head and Neck
  • Locally Advanced Head and Neck Squamous Cell Carcinoma
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms



University of Pittsburgh Cancer InstitutePittsburgh, Pennsylvania  15213