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Identification of Gene Expression Signature for Panitumumab Sensitivity in Untreated Locally Advanced SCCHN (TOP0901)

Primary Purpose

Squamous Cell Carcinoma of the Head and Neck

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Panitumumab

Surgery

Radiation Therapy

About this trial

This is an interventional treatment trial for Squamous Cell Carcinoma of the Head and Neck focused on measuring SCCHN, untreated, Stage III or IVa-b (M0)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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
Candidate for definitive surgery or radiation based therapy.
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
Measurable or evaluable disease
Eastern Cooperative Oncology Group (ECOG) 0-1
≥18 years of age
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)
Negative serum pregnancy test ≤7 days before starting panitumumab (for women of childbearing potential only)
Competent to comprehend, sign, and date a written informed consent form
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:

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
Primary tumor of the nasopharynx (nasopharyngeal cancer), sinuses, salivary gland, or skin. (Squamous cell carcinoma arising in/near nasopharynx is eligible)
Prior radiotherapy in planned field if it prevents standard radiotherapy dose and field
Prior radiation for head & neck cancer
Prior anti-EGFR antibody therapy (e.g., cetuximab) or treatment with small molecule EGFR inhibitors (e.g., gefitinib, erlotinib, lapatinib)
Prior anti-cancer treatment with: chemotherapy, hormonal therapy, immunotherapy, experimental or approved proteins/antibodies within the past 5 years.
Prior systemic chemotherapy for study cancer
Investigational agent or therapy ≤30 days before enrollment and/or have not recovered from such side effects
Continued chronic use of immunosuppressive agents during the clinical trial period (e.g., methotrexate and cyclosporine), corticosteroids are allowed
Clinically significant cardiovascular disease (including myocardial infarction (MI), unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤6 months before enrollment
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
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
Unwilling or unable to comply with study requirements
Pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment
Known positive test(s) for HIV infection
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.
Known allergy/hypersensitivity to any component of the study treatment(s)
Infection requiring intravenous antibiotics for any uncontrolled infection ≤14 days prior to enrollment
Subjects on anticoagulant therapy. Aspirin and other anti-platelet agents will not be defined as anticoagulant therapy for this study

Sites / Locations

University of North Carolina at Chapel Hill
Duke University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Surgery

Radiation Therapy

Arm Description

Patients who underwent surgery after research PET/CT scans and subsequent radiation therapy with panitumumab administration

Patients who underwent radiation therapy only, in conjunction with panitumumab therapy.

Outcomes

Primary Outcome Measures

Change in Tumor (Primary Tumor and Lymph Node) Response and Progression Between Pre- and Post- Panitumumab Therapy

The aim of this outcome measure was to identify a gene expression signature that predicts response to panitumumab in untreated locally advanced squamous cell cancer of the head / neck (SCCHN). Response and progression were evaluated using the largest percentage change among the cases: 1) Pre-panitumumab PET scan activity, and/or; 2) Pre-panitumumab radiologic measurement compared to post-panitumumab measurement and/or; 3) Pre-panitumumab direct measurement of tumor / lymph node compared to post-panitumumab direct measurement of tumor / lymph node. Response and progression were evaluated in this single study using the criteria "changes in only the largest diameter (unidimensional measurement) of the tumor lesions were defined" in the same manner as in RECIST 1.1. No results are reported as only 2 of the 6 subjects had fresh tissue collected after the first dose of panitumumab. The study was amended to remove the biopsy procedure due to the potential risk for the participants.

Secondary Outcome Measures

Nine (9) Month Progression Free Survival (PFS)

Nine month progression-free survival (PFS) was defined from the time from enrollment to the first date of disease progression or death as a result of any cause. Progression was defined in the same manner as in RECIST 1.1: At least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5mm (the appearance of one or more new lesions is also considered progression). Time was censored at the date of the last follow-up visit for subjects who were still alive and have not progressed. The 9 month PFS rate is a percentage, representing the fraction of treated subjects who, after 9 months, are disease free or alive.

Nine (9) Month Overall Survival (OS)

Overall survival (OS) was defined as from the time of enrollment to the date of death resulting from any cause. Time as censored at the date of the last follow-up visit for subjects who were still alive. The 9-month OS rate is a percentage, representing the fraction of treated subjects who, after 9 months, are alive.

Full Information

NCT ID

NCT01305772

First Posted

February 14, 2011

Last Updated

August 19, 2014

Sponsor

Neal Ready

Collaborators

Amgen

1. Study Identification

Unique Protocol Identification Number

NCT01305772

Brief Title

Identification of Gene Expression Signature for Panitumumab Sensitivity in Untreated Locally Advanced SCCHN

Acronym

TOP0901

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)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2014

Overall Recruitment Status

Terminated

Why Stopped

This study was terminated for low accrual.

Study Start Date

January 2011 (undefined)

Primary Completion Date

March 2012 (Actual)

Study Completion Date

May 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Neal Ready

Collaborators

Amgen

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Squamous Cell Carcinoma of the Head and Neck

Keywords

SCCHN, untreated, Stage III or IVa-b (M0)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

6 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Surgery

Arm Type

Experimental

Arm Description

Patients who underwent surgery after research PET/CT scans and subsequent radiation therapy with panitumumab administration

Arm Title

Radiation Therapy

Arm Type

Active Comparator

Arm Description

Patients who underwent radiation therapy only, in conjunction with panitumumab therapy.

Intervention Type

Drug

Intervention Name(s)

Panitumumab

Other Intervention Name(s)

Vectibix®, ABX-EGF

Intervention Description

Single dose Panitumumab 9mg/kg IV (in the vein) prior to definitive therapy (surgery or radiation therapy). Two additional doses of panitumumab 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.

Intervention Type

Procedure

Intervention Name(s)

Surgery

Intervention Description

Second biopsy was taken from surgical resection tissue (when possible obtained pre and post panitumumab biopsies from the same site).

Intervention Type

Procedure

Intervention Name(s)

Radiation Therapy

Other Intervention Name(s)

Intervention Description

Radiation therapy was initiated within 8 weeks after surgery, or as soon as possible.

Primary Outcome Measure Information:

Title

Change in Tumor (Primary Tumor and Lymph Node) Response and Progression Between Pre- and Post- Panitumumab Therapy

Description

Time Frame

Baseline to 2 years

Secondary Outcome Measure Information:

Title

Nine (9) Month Progression Free Survival (PFS)

Description

Time Frame

9 months

Title

Nine (9) Month Overall Survival (OS)

Description

Time Frame

9 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 Candidate for definitive surgery or radiation based therapy. 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 Measurable or evaluable disease Eastern Cooperative Oncology Group (ECOG) 0-1 ≥18 years of age Adequate organ function neutrophil count (ANC or AGC) ≥1.5 x 109/L Platelet count ≥75 x 109/L Hemoglobin ≥9.0 g/dL Creatinine ≤1.5x upper limit of normal (ULN) Hepatic enzymes (AST, ALT)≤2.5x ULN, Total Bilirubin <1.5x ULN Magnesium ≥ Lower limit of Normal (LLN) Negative serum pregnancy test ≤7 days before starting panitumumab (for women of childbearing potential only) Competent to comprehend, sign, and date a written informed consent form 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: History of other malignancy within past 2 years, except: Malignancy treated with curative intent and with no known active disease Adequately treated non-melanomatous skin cancer or lentigo maligna with no evidence of disease Adequately treated cervical carcinoma in situ with no evidence of disease Prostatic intraepithelial neoplasia with no evidence of prostate cancer Primary tumor of the nasopharynx (nasopharyngeal cancer), sinuses, salivary gland, or skin. (Squamous cell carcinoma arising in/near nasopharynx is eligible) Prior radiotherapy in planned field if it prevents standard radiotherapy dose and field Prior radiation for head & neck cancer Prior anti-EGFR antibody therapy (e.g., cetuximab) or treatment with small molecule EGFR inhibitors (e.g., gefitinib, erlotinib, lapatinib) Prior anti-cancer treatment with: chemotherapy, hormonal therapy, immunotherapy, experimental or approved proteins/antibodies within the past 5 years. Prior systemic chemotherapy for study cancer Investigational agent or therapy ≤30 days before enrollment and/or have not recovered from such side effects Continued chronic use of immunosuppressive agents during the clinical trial period (e.g., methotrexate and cyclosporine), corticosteroids are allowed Clinically significant cardiovascular disease (including myocardial infarction (MI), unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤6 months before enrollment 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 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 Unwilling or unable to comply with study requirements Pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment Known positive test(s) for HIV infection 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. Known allergy/hypersensitivity to any component of the study treatment(s) Infection requiring intravenous antibiotics for any uncontrolled infection ≤14 days prior to enrollment Subjects on anticoagulant therapy. Aspirin and other anti-platelet agents will not be defined as anticoagulant therapy for this study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Neal Ready, MD, PhD

Organizational Affiliation

Duke University

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of North Carolina at Chapel Hill

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27514

Country

United States

Facility Name

Duke University Medical Center

City

Durham

State/Province

North Carolina

ZIP/Postal Code

27710

Country

United States

12. IPD Sharing Statement

Learn more about this trial

Identification of Gene Expression Signature for Panitumumab Sensitivity in Untreated Locally Advanced SCCHN

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