Identification of Gene Expression Signature for Panitumumab Sensitivity in Untreated Locally Advanced SCCHN
Identification of Gene Expression Signature for Panitumumab Sensitivity in Untreated Locally Advanced SCCHN
The purpose of this study was 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 was added to standard adjuvant or primary radiation therapy. There were subjects
 that receive surgery followed by therapy and subjects that receive radiation therapy without
 surgery.

 Subjects entering this study had locally advanced disease that can be treated with surgery
 and/or radiation therapy. Fresh frozen tumor tissue were available for genomics analysis
 prior to initiating panitumumab therapy. If fresh frozen tissue was not available at time of
 consent, a biopsy was required to participate in this trial.
The trial was initiated 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. 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 received 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 Radiation Therapy (RT) based therapy was based on best medical practice by the treating
 physician per National Comprehensive Cancer Network (NCCN) guidelines at www.nccn.org.

 Response to panitumumab monotherapy before surgery or radiation was 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 was then developed by analyzing
 gene expression in panitumumab sensitive versus resistant tumors. Identification of a gene
 expression profile for tumor sensitivity allowed 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 standardized uptake value (SUV)
 level or objective evidence of tumor response (by CT scan or direct measurement) was the
 basis for examining the activity of panitumumab by means of identifying a gene expression
 signature that predicted response in this patient population. Therefore, PET scan SUV levels
 was assessed at baseline prior to any treatment. If a baseline PET/CT was obtained and a
 lesion identified with SUV level ≥6, an additional pre-treatment research PET/CT was
 performed after consent (prior to dose #1 panitumumab. A second research PET/CT was also
 obtained after the first dose of panitumumab as part of this research study. If no baseline
 PET/CT had been obtained, a research PET was obtained pre-treatment; if SUV level ≥6 an
 additional research PET was obtained after the first dose of panitumumab.

 All subjects underwent imaging, biopsy and a single dose of panitumumab 9mg/kg IV. Two to
 three weeks after panitumumab, imaging was repeated and a second biopsy was obtained (at
 surgery for surgery patients) and an optional biopsy for patients receiving RT. Subjects
 received 2 additional doses of panitumumab during their standard therapy.
Inclusion Criteria:

 1. Untreated, suspected or histologically documented locally advanced clinical stage III
 or IVa-b(M0)SCCHN, no evidence of distant metastases. Prior surgery with diagnosis of
 SCCHN acceptable

 2. Candidate for definitive surgery or radiation based therapy.

 3. Fresh frozen tumor tissue must be available for genomic analysis and must pass RNA
 Quality Control prior to research PET/CT #1 and/or initiating panitumumab

 4. Measurable or evaluable disease

 5. Eastern Cooperative Oncology Group (ECOG) 0-1

 6. ≥18 years of age

 7. Adequate organ function

 1. neutrophil count (ANC or AGC) ≥1.5 x 109/L

 2. Platelet count ≥75 x 109/L

 3. Hemoglobin ≥9.0 g/dL

 4. Creatinine ≤1.5x upper limit of normal (ULN)

 5. Hepatic enzymes (AST, ALT)≤2.5x ULN, Total Bilirubin <1.5x ULN

 6. Magnesium ≥ Lower limit of Normal (LLN)

 8. Negative serum pregnancy test ≤7 days before starting panitumumab (for women of
 childbearing potential only)

 9. Competent to comprehend, sign, and date a written informed consent form

 10. Sexually active males & females of reproductive potential must agree to use adequate
 method of contraception during treatment & for 6 months after study drug stopped

 Exclusion Criteria:

 1. History of other malignancy within past 2 years, except:

 1. Malignancy treated with curative intent and with no known active disease

 2. Adequately treated non-melanomatous skin cancer or lentigo maligna with no
 evidence of disease

 3. Adequately treated cervical carcinoma in situ with no evidence of disease

 4. Prostatic intraepithelial neoplasia with no evidence of prostate cancer

 2. Primary tumor of the nasopharynx (nasopharyngeal cancer), sinuses, salivary gland, or
 skin. (Squamous cell carcinoma arising in/near nasopharynx is eligible)

 3. Prior radiotherapy in planned field if it prevents standard radiotherapy dose and
 field

 4. Prior radiation for head & neck cancer

 5. Prior anti-EGFR antibody therapy (e.g., cetuximab) or treatment with small molecule
 EGFR inhibitors (e.g., gefitinib, erlotinib, lapatinib)

 6. Prior anti-cancer treatment with: chemotherapy, hormonal therapy, immunotherapy,
 experimental or approved proteins/antibodies within the past 5 years.

 7. Prior systemic chemotherapy for study cancer

 8. Investigational agent or therapy ≤30 days before enrollment and/or have not recovered
 from such side effects

 9. Continued chronic use of immunosuppressive agents during the clinical trial period
 (e.g., methotrexate and cyclosporine), corticosteroids are allowed

 10. Clinically significant cardiovascular disease (including myocardial infarction (MI),
 unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac
 arrhythmia) ≤6 months before enrollment

 11. History of interstitial lung disease e.g., pneumonitis or pulmonary fibrosis or
 evidence of interstitial lung disease on baseline chest CT scan. Patients with CT scan
 findings consistent with lung scarring from chronic obstructive pulmonary disease
 (COPD) or previous infection are eligible

 12. History of any medical or psychiatric condition or laboratory abnormality that in the
 opinion of the investigator may increase the risk associated with the study
 participation or investigational product(s) administration or may interfere with the
 interpretation of the results

 13. Unwilling or unable to comply with study requirements

 14. Pregnant or breast feeding, or planning to become pregnant within 6 months after the
 end of treatment

 15. Known positive test(s) for HIV infection

 16. Major surgery within 2 weeks of enrollment. Staging endoscopy with
 biopsy/tonsillectomy for head & neck cancer, tracheostomy, and/or gastrostomy tube
 placement eligible one day after procedure. May consent to tissue collection biopsy
 pre-endoscopy/minor surgery and then begin protocol therapy one day after procedure.

 17. Known allergy/hypersensitivity to any component of the study treatment(s)

 18. Infection requiring intravenous antibiotics for any uncontrolled infection ≤14 days
 prior to enrollment

 19. Subjects on anticoagulant therapy. Aspirin and other anti-platelet agents will not be
 defined as anticoagulant therapy for this study