Early Prediction of Therapeutic Response to Targeted Therapy in Stage IIIB/IV or Recurrent Lung Cancer Patients
This exploratory clinical study is designed to obtain pre-therapeutic imaging assessments using positron emission tomography (PET) imaging in 21 patients with Stage IIIB/IV or recurrent non-small cell lung cancer (NSCLC) and an early post therapy assessment at baseline and at various early time points (2 weeks in 7 patients, 4 weeks in 7 patients, and 6 weeks in 7 patients) after institution of erlotinib (anti-EGFR) (Tarceva) and bevacizumab (anti-VEGF) (Avastin) for first-line treatment of Stage IIIB/IV or recurrent non-squamous NSCLC. The proposed PET imaging and blood derived biomarkers trial is a companion study to an approved therapeutic trial (IRB# 24377). The therapeutic trial of erlotinib (Tarceva) and bevacizumab (Avastin) for first-line treatment of Stage IIIB/IV or recurrent lung cancer with drug costs exceeding $150,000 per patient/year (study drug budget exceeds $5 million) was funded for study at the HCI and the HICCP, statewide trial network. The proposed imaging study has been funded by the University of Utah Synergy Grant Program. The clinical imaging biomarkers will include an assessment of tumor metabolism [Banrasch 1986, Frauwirth 2002, Garber 2006, Kelloff 2005, Pauwels 1998, Semenza 2001, Smith 1999, Smith 2000, Sokoloff 1977, Warburg 1956, Weber 1977A, Weber] (dynamic FDG-PET); tumor proliferation [Rasey 2002,Shields 2001,Shields 1998, Vesselle 2002, Schwartz 2003] (dynamic FLT-PET); tumor blood flow and perfusion( H215O-PET)[Lodge 2000]; and tumor blood volume of distribution ( H215O -PET)[Lodge 2000] in the same patient at baseline and then in the same patient at one of the post therapy time points (2 weeks, 4 weeks, or 6 weeks). The investigators hypothesize that by using a set of imaging derived biomarkers and biomarkers from blood they can predict response, either prior to or at an earlier time point than would normally be determined with standard imaging techniques, in patients with lung cancer receiving combined bevacizumab and erlotinib.
|Study Design:||Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
|Official Title:||Development of an Integrated Molecular Biomarker ofEarly Prediction of Therapeutic Response to Targeted Therapy in Stage IIIB/IV or Recurrent Lung Cancer Patients Using Imaging Assessments and Genomic Modeling|
- Provide reliable validated, PET imaging derived biomarkers and serum derived biomarkers for a better understanding of early clinical benefit from Avastin/Tarceva therapy, efficacy during Avastin/Tarceva therapy, and prognosis or other long term outcomes. [ Time Frame: December 2011 ] [ Designated as safety issue: No ]
|Study Start Date:||January 2008|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||December 2013 (Final data collection date for primary outcome measure)|
Experimental: All patients
All participants enrolled.
Radiation: PET Imaging
Patients will receive an FLT-PET scan, FDG-PET scan, a H215O-PET scan, and have a blood sample (15 cc, approximately 3 teaspoons) drawn for the genetic and protein studies. These studies will be done before patients begin taking erlotinib and bevacizumab.
Other Name: FLT-PET scan, FDG-PET scan, a H215O-PET scan
Hide Detailed Description
Non-Small Cell Lung Cancer Non- small cell lung cancer is the most common cause of cancer mortality in the United States [Jermal, 2007]. Surgery can be curative for patients with stages I and II disease and chemoradiation for curative intent can be administered to selected patients with stage III disease in the setting of adequate performance status, minimal comorbid disease and absence of weight loss. Adjuvant therapy improves survival, but the relapse rate is high and may approach 80% for subsets of patients with presumed "curable disease". Consequently, 85% of patients diagnosed with NSCLC will ultimately die of uncontrolled systemic disease. Systemic chemotherapy for treatment of metastatic disease, offers palliative benefit, improves survival, has substantial side effects, but is not curative. Improved systemic therapy with a greater therapeutic index due to greater efficacy or fewer side effects is sorely needed. Bevacizumab and/or erlotinib demonstrate these features.
Therapeutic Drugs (Erlotinib and Bevacizumab) The therapeutic trial, which this molecular imaging and serum biomarker trial will compliment, will study the combination of erlotinib and bevacizumab as first-line treatment for patients with non-squamous non-small cell lung cancer (NSCLC). This will be the first ever study where conventional chemotherapy will not be used as first-line treatment in NSCLC. Both erlotinib, as a single agent after chemotherapy progression [Shepherd 2005], and bevacizumab, in combination with chemotherapy [Sandler 2006], have been approved for the treatment of metastatic NSCLC. This is a multi-center trial via Huntsman Cancer Institute - Intermountain Cancer Care Program, phase II, single stage, of erlotinib (150 mg/day) and bevacizumab (15 mg/kg IV every 21 days) for patients with non-squamous, NSCLC without brain metastases or significant hemoptysis who have not received conventional chemotherapy as treatment for systemic or relapsed disease. Study treatment will be continued until symptomatic or objective progression. Patients progressing on or after this combination will subsequently receive conventional chemotherapy with bevacizumab at the discretion of the patient and treating physician. The study will be followed by the Data and Safety Monitoring Committee of the HCI and will enroll 40 patients. An interim safety analysis is scheduled after 20 patients have been accrued.
For purposes of defining response the following criteria are used for all target lesions: complete response—the disappearance of all target lesions; partial response—at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter; progressive disease—at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions; stable disease—neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started.
The primary exploratory objectives of the study are:
- Provide a reliable and validated cadre of PET imaging derived biomarkers and serum derived biomarkers that yield a better understanding of: 1) early clinical benefit from Avastin and Tarceva therapy, 2) efficacy during Avastin and Tarceva therapy, and 3) prognosis or other long term outcomes.
- Reveal a more detailed understanding of: (1) the in vivo biologic mechanisms of Avastin and Tarceva in lung cancer and (2) information on why particular functional imaging assays and genomic biomarker profiles are seen in treated patients.
- Reveal a more detailed understanding of how the combination of molecular imaging derived biomarkers in combination with gene expression profiles/biomarkers will be potentially useful to physicians for decision making and for explanation of efficacy or outcomes for patients with cancer.
- Predict which patients may benefit from combined Avastin and Tarceva therapy.
- Determine early in the course of treatment whether Avastin and Tarceva will be efficacious and whether the imaging derived biomarkers in combination with blood derived biomarkers can be used in the future in patients with other types of malignancies to predict early response and efficacy.
|United States, Utah|
|Huntsman Cancer Institute|
|Salt Lake City, Utah, United States, 84112|
|Principal Investigator:||John M Hoffman, MD||Huntsman Cancer Institute|