Identification of Gene Expression Signature for Panitumumab Sensitivity in Untreated Locally Advanced SCCHN (TOP 0901)
The purpose of this study is to identify which cancer-related genes are turned on or turned off in order to determine how well a patient will respond to the study drug, panitumumab. Panitumumab will be added to standard adjuvant or primary radiation therapy. There will be those subjects that receive surgery followed by therapy and subjects that receive radiation therapy without surgery.
Subjects entering this study must have locally advanced disease that can be treated with surgery and/or radiation therapy. Fresh frozen tumor tissue must be available for genomics analysis prior to initiating panitumumab therapy. If fresh frozen tissue is not available at time of consent, a biopsy will be required to participate in this trial.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Identification of a Gene Expression Signature Profile for Panitumumab Sensitivity in Untreated Locally Advanced Squamous Cell Cancer of the Head and Neck (SCCHN)|
- Identify a gene expression signature profile biomarker that predicts for sensitivity/response to panitumumab in untreated locally advanced SCCHN. [ Time Frame: 2 years ] [ Designated as safety issue: No ]Plan will be to develop an Affymetrix chip based gene signature model by analyzing gene expression in panitumumab sensitive versus resistant tumors. Identification of a gene expression profile for tumor sensitivity would allow for prospective trials treating patient populations enriched for likelihood of clinical benefit from panitumumab therapy. It is also possible that a gene signature profile for panitumumab responsiveness identified in SCCHN could be used as a biomarker in other epithelial cancers.
- 1. Compare a metagene-based gene expression signature for EGFR pathway activation to other previously identified markers/models representative of EGFR pathway activation. [ Time Frame: 2 years ] [ Designated as safety issue: No ]The association between response to panitumumab treatment and the metagene-based gene expression signature for EGFR pathway activation will be assessed using Spearman rank correlation coefficient. If a significant association is observed, the predictive value of the EGFR signature will be ascertained in an exploratory manner using receiver operator characteristic (ROC) curves.
- Compare gene expression for EGFR pathway before and after treatment with panitumumab. [ Time Frame: 2 years ] [ Designated as safety issue: No ]Changes in EGFR pathway activation will be evaluated using descriptive statistics and a significant trend will be evaluated with the non-parametric Wilcoxon signed rank test.
- Compare the response rates, progression-free survival and overall survival rates of loco-regional disease control maintained for 2 years to historical controls selected from two previously conducted(ongoing)trials with locally advanced SCCHN. [ Time Frame: 4 years ] [ Designated as safety issue: No ]Response/progression evaluated using % change in:1)pre-panitumumab PET scan activity compared to post-panitumumab activity,and2)pre-panitumumab radiologic measurement compared to post-panitumumab measurement and/or3)pre-panitumumab direct measurement of tumor/lymph node compared to post-panitumumab direct measurement of tumor/lymph node. This study will use "changes in only the largest diameter (unidimensional measurement) of the tumor lesions will be defined" in the same manner as in RECIST 1.1.Radiologic response or objective response by direct measurement will be defined using RECIST 1.1.
- Exploratory DNA and biomarker analysis of pretreatment blood sample. [ Time Frame: 2 year ] [ Designated as safety issue: No ]This work will be exploratory and hypothesis generating in examining alterations both genome-wide and in specific targets such as epidermal growth factor receptor (EGFR).
- Profile tumor tissue DNA for any genetic alterations as compared to normal tissue. [ Time Frame: 2 years ] [ Designated as safety issue: No ]Tumor tissue DNA will be used for investigation of genetic alterations as compared to normal tissue. This work will be exploratory and hypothesis generating in examining alterations both genome-wide and in specific targets
|Study Start Date:||January 2011|
|Estimated Study Completion Date:||February 2015|
|Estimated Primary Completion Date:||February 2013 (Final data collection date for primary outcome measure)|
Single dose Panitumumab 9mg/kg IV (in the vein) prior to definitive therapy (surgery or radiation therapy). Two additional doses of pantitumumab 9mg/kg IV may be given at weeks 1 & 4 of RT alone or weeks 1 & 4 of cisplatin/RT if they tolerated first dose of panitumumab.
This trial will attempt to identify a gene expression signature profile biomarker for panitumumab sensitivity in locally advanced, untreated SCCHN. SCCHN expresses or over expresses EGFR in >90% of tumors. Panitumumab is a fully human IgG2 monoclonal antibody approved for the treatment of epidermal growth factor receptor (EGFR) expressing previously treated metastatic colorectal cancer. It competes with endogenous ligands such as epidermal growth factor and tumor growth factor-α and blocks stimulation of the EGFR.9 Preclinical experiments have shown that panitumumab has both direct anti-tumor activity and can activate a cellular immune response to SCCHN.This study provides the opportunity to better define the population of patients that would benefit from EGFR inhibition in SCCHN.
Patients will receive single agent panitumumab in a "window of opportunity" design prior to definitive surgical or radiation therapy. The decision to treat primarily with either surgery or RT based therapy will be based on best medical practice by the treating physician per NCCN guidelines at www.nccn.org.
Response to panitumumab monotherapy before surgery or radiation will be evaluated as a continuous variable, and a median split of patients will be used to develop a signature of drug responsiveness. An Affymetrix chip based gene signature model will then be developed by analyzing gene expression in panitumumab sensitive versus resistant tumors. Identification of a gene expression profile for tumor sensitivity would allow for prospective trials treating patient populations enriched for likelihood of clinical benefit from panitumumab therapy. It is also possible that a gene signature profile for panitumumab responsiveness identified in SCCHN could be used as a biomarker in other epithelial cancers.
Tumor response as measured by percentage decrease in PET scan SUV level or objective evidence of tumor response (by CT scan or direct measurement) will be the basis for examining the activity of panitumumab by means of identifying a gene expression signature that predicts response in this patient population. Therefore, PET scan SUV levels will be assessed at baseline prior to any treatment. If a baseline PET/CT is obtained and a lesion identified with SUV level ≥6, an additional pre-treatment research PET/CT will be performed after consent (prior to dose #1 panitumumab. A second research PET/CT will also be obtained after the first dose of panitumumab as part of this research study. If no baseline PET/CT has been obtained, a research PET will be obtained pre-treatment, if SUV level ≥6 an additional research PET will be obtained after the first dose of panitumumab.
All subjects will undergo imaging, biopsy and a single dose of panitumumab 9mg/kg IV. Two to three weeks after panitumumab, imaging will be repeated and a second biopsy will be obtained (at surgery for surgery patients) and an optional biopsy for patients receiving RT. Subjects may receive 2 additional doses of panitumumab during their standard therapy.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01305772
|Contact: Deb Shoemaker, RNemail@example.com|
|Contact: Traci Foster, RNfirstname.lastname@example.org|
|United States, North Carolina|
|University of North Carolina at Chapel Hill||Not yet recruiting|
|Chapel Hill, North Carolina, United States, 27514|
|Contact: D. N. Hayes, MD, MPH email@example.com|
|Sub-Investigator: Marion Couch, MD|
|Sub-Investigator: Bhisham Chera, MD|
|Duke University Medical Center||Recruiting|
|Durham, North Carolina, United States, 27710|
|Contact: Neal Ready, MD, PhD 919-681-6932 firstname.lastname@example.org|
|Sub-Investigator: David Brizel, MD|
|Sub-Investigator: Richard Scher, MD|
|Sub-Investigator: Jenny Hoang, MD|
|Sub-Investigator: Frank Dunphy, MD|
|Sub-Investigator: Michael Datto, MD, PhD|
|Sub-Investigator: David Yoo, MD|
|Sub-Investigator: Walter Lee, MD|
|Principal Investigator:||Neal Ready, MD, PhD||Duke University|