Salt Lake City,
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
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.
1. All subjects must be enrolled in the the therapeutic trial (IRB # 24377) with
non-squamous non-small cell lung cancer (NSCLC) treated with combined erlotinib
(Tarceva) (150 mg/day)and bevacizumab (Avastin) (15mg/kg q 21 days) as first line
2. Adults must have radiological evidence of Stage IIIB/IV or recurrent non-squamous
non-small cell carcinoma. The Stage IIIB/IV or Recurrent lesion must be in a location
that includes a large arterial vessel to allow for determination of the H215O
arterial input function. A previous histological diagnosis of NSCLC would be required
prior to institution of therapy. Only clinically indicated biopsy and/or surgery for
determination of Stage IIIB/IV or recurrent disease will be done and surgery is
incidental to inclusion in the protocol.
3. Patients must be 18 years or older for inclusion in this study. Since there is no
experience with [F-18]FLT in children and it would be inappropriate to study
individuals under the age of 18 until more safety data is available.
4. After entry into the study, patients are expected to be followed for at least 2
months as part of standard of care.
5. All patients, or their legal guardians, must sign a written informed consent and
HIPAA authorization in accordance with institutional guidelines.
6. The patient, if female, must be postmenopausal for a minimum of one year or
surgically sterile, or on one of the following methods of birth control for a minimum
of one month prior to entry into this study: IUD, oral contraceptives, Depo-Provera
or Norplant. These criteria can be waived at the discretion of the investigator if
the patient's tumor is considered life threatening and the one month wait required is
not in the best interest of the patient. Negative pregnancy test is accepted.
7. Pre-treatment laboratory tests for patients receiving [F-18]FLT must be performed
within 21 days prior to study entry. These must be less than 4 times below or above
the upper or lower limit range for the respective laboratory test. The patients have
Stage IIIB/IV or recurrent NSCLC and therefore many routine laboratory tests may not
be within the typical normal range. Using a factor of 4 times above or below the
upper or lower value for the normal range for laboratory test will assure ability to
recruit patients and maintain safety. In those instances where a value of 4X above
the normal range would be inappropriate for inclusion (prothrombin time and partial
thromboplastin time) then a value of 2.5X will be used for these two laboratory
tests. In those instances when the prothrombin time or partial thromboplastin time
are greater than 2.5X the upper limit of normal then such a patient would not be
enrolled. The 4X value will be used for all laboratory values except prothrombin time
and partial thromboplastin time which cannot be above or below 2.5 times the upper or
lower limit of normal (Appendix E, [F-18]FLT Laboratory Study Results). A negative
serum pregnancy test is required within 2 days prior to the PET studies.
8. Pre-treatment radiological clinical scans/studies (Gd- enhanced MRI or CT to document
Stage IIIB/IV or recurrent NSCLC) must be performed within 30 days of study entry.
1. Patients will be receiving erlotinib (Tarceva) (150 mg/day)and bevacizumab (Avastin)
(15mg/kg q 21 days) as part of the therapeutic trial. Enrollment may not occur if the
patient does not meet the enrollment criteria for the therapeutic trial
2. Patients with known allergic or hypersensitivity reactions to previously administered
radiopharmaceuticals. Patients with significant drug or other allergies or autoimmune
diseases may be enrolled at the Investigator's discretion.
3. Patients who are pregnant or lactating or who suspect they might be pregnant.
4. Adult patients who require monitored anesthesia for PET scanning.
5. HIV positive patients due to the previous toxicity noted with FLT.
6. Claustrophobia or inability to remain stationary within the PET scanner for 90