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
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
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.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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.
John M Hoffman, MD
Huntsman Cancer Institute
United States: Food and Drug Administration
|Huntsman Cancer Institute||Salt Lake City, Utah 84112|