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.

Eligibility Criteria:
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