Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01515137 |
| Other study ID # |
05-045 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
November 2005 |
| Est. completion date |
September 2014 |
Study information
| Verified date |
January 2016 |
| Source |
University of Pittsburgh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This trial was originally designed and powered to compare biomarker modulation in the
neo-adjuvant setting (erlotinib versus erlotinib plus sulindac versus placebo) with clinical
response to erlotinib in the adjuvant setting. Since implementing the trial in late 2005, The
investigators have encountered significant obstacles to implementing the adjuvant therapy
phase of the trial.
- Barriers included:
1. disease recurrence
2. patient refusal to take the agent
3. patient refusal to travel to Pittsburgh for clinical evaluations.
Given the institutional challenges to implement and complete the adjuvant portion, the
investigators have decided to change the primary endpoint to a biomarker modulation endpoint.
To achieve this goal, the investigators determined that they needed 39 paired tissue
specimens (see statistical justification below).
The central hypothesis to be tested in this study is that persistent activation of parallel
and/or downstream pathways contributes to tumor progression in the setting of EGFR blockade.
While not all head and neck squamous cell carcinoma (HNSCC) patients will respond to EGFR
targeting, the optimal strategy to identify those subjects whose tumors are sensitive to EGFR
inhibition remains unknown.
The primary objective is centered around the concept of tumor biomarkers which may be
modulated by EGFR and Cox-2 inhibitors and may serve as future therapeutic targets for
therapy. To this end patients on this trial will be randomly assigned to one of three arms to
receive either Tarceva, Tarceva plus sulindac, or a placebo 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.
Sample size for the primary objective
Modification of Statistical Design:
The primary endpoint is the difference between pre (biopsy) and post (surgery). There are 3
hypotheses of interest: (1) placebo vs erlotinib alone, (2) placebo versus erlotinib plus
sulindac, and (3) erlotinib vs erlotinib + sulindac. With a randomization in a 3:5:5 ratio,
we have 88% power, alpha = .01 for an omnibus test to show between-group differences of 1 log
exist. This requires 39 patients. Basically, 39 patients will provide the ability to detect a
one log difference between any 2 of the 3 groups in pre-post change.
Description:
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.
