A Phase II Study of Capecitabine, Carboplatin, and Bevacizumab for Metastatic or Unresectable Gastroesophageal Junction and Gastric Adenocarcinoma
Subjects must be treated at Stanford University Medical Center for the entire length of
1. Patients with histologically or cytologically confirmed adenocarcinoma of the GEJ or
2. Patients must be deemed unresectable due to involvement of critical vasculature or
adjacent organ invasion. If unresectable, patients must show evidence of disease
progression prior to enrollment.
3. Patients with prior surgical resection who develop radiological or clinical evidence
of metastatic cancer do not require separate histological or cytological confirmation
of metastatic disease unless an interval of > 5 years has elapsed between the primary
surgery and the development of metastatic disease. Clinicians should consider biopsy
of lesions to establish diagnosis of metastatic disease if there is substantial
clinical ambiguity regarding the nature or source of apparent metastases.
4. Prior carboplatin as neoadjuvant or adjuvant therapy will be allowed if >= 6 months
from the time of study entry.
5. If patients use aspirin (>325mg/day) or NSAIDS at the time of enrollment, they must
have a 10 day washout period prior to beginning protocol treatment.
6. Low molecular weight heparin (or its equivalent, excluding warfarin) will be allowed
for treatment of venous thromboembolic events if patients have no evidence of
bleeding on full-dose anticoagulation.
7. Patients must have a primary or metastatic lesion measurable in at least one
dimension by Modified RECIST criteria (see Section 11.2.3) within 4 weeks prior to
entry of study
8. Patients must have ECOG performance status of 0-1
9. Patients must be >= 18 years of age
10. Laboratory values <= 2 weeks prior to randomization:
- Absolute Neutrophil Count (ANC) >= 1.5 x 109/L (>= 1500/mm3)
- Platelets (PLT) >= 100 x 109/L (>= 100,000/mm3)
- Hemoglobin (Hgb) >= 9 g/dL
- Serum creatinine <= 1.5 x ULN
- Serum bilirubin <= 1.5 x ULN (<= 3.0 x ULN if liver metastases present)
- Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) <=
3.0 x ULN (<= 5.0 x ULN if liver metastases present). Note: ERCP or
percutaneous stenting may be used to normalize the liver function tests.
11. Life expectancy >= 12 weeks
12. Inclusion and exclusion criteria for DCE-MRI and DWI imaging will be determined by CT
scan as part of routine post-chemotherapy imaging. Subjects will be eligible if one
liver metastasis is greater than 1 cm in size. Participation in the DCE-MRI and DWI
correlate is not required for eligibility.
13. Ability to give written informed consent according to local guidelines
1. Disease-Specific Exclusions
1. Prior chemotherapy for metastatic disease
2. Prior full field radiotherapy <= 4 weeks or limited field radiotherapy <= 2
weeks prior to enrollment. Patients must have recovered from all
therapy-related toxicities. The site of previous radiotherapy should have
evidence of progressive disease if this is the only site of disease.
3. Prior biologic or immunotherapy <= 2 weeks prior to registration. Patients must
have recovered from all therapy-related toxicities
4. Prior therapy with anti-VEGF agents
5. If history of other primary cancer, subject eligible only if she or he has:
- Curatively resected non-melanomatous skin cancer
- Curatively treated cervical carcinoma in situ
- Other primary solid tumor curatively treated with no known active disease
present and no treatment administered for the last 3 years
6. Concurrent use of other investigational agents and patients who have received
investigational drugs <= 4 weeks prior to enrollment.
7. Hypersensitivity to capecitabine, fluorouracil, or any component of the
formulation and or a known deficiency of dihydropyrimidine dehydrogenase.
2. General Medical Exclusions
1. Subjects known to have chronic or active hepatitis B or C infection
2. History of any medical or psychiatric condition or laboratory abnormality that
in the opinion of the investigator may increase the risks associated with study
participation or study drug administration or may interfere with the conduct of
the study or interpretation of study results
3. Male subject who is not willing to use adequate contraception upon enrollment
into this study and for 6 months following the last dose of second-line
4. Female subject (of childbearing potential, post-menopausal for less than 6
months, not surgically sterilized, or not abstinent) who is not willing to use
an oral, patch or implanted contraceptive, double-barrier birth control, or an
IUD during the course of the study and for 6 months following the last dose of
5. Female subject who is breast-feeding or who has positive serum pregnancy test 72
hours prior to randomization
6. Pleural effusion or ascites that causes respiratory compromise (>= CTCAE grade 2
7. Any of the following concurrent severe and/or uncontrolled medical conditions
within 24 weeks of enrollment which could compromise participation in the study:
- Unstable angina pectoris
- Symptomatic congestive heart failure
- Myocardial infarction <= 6 months prior to registration and/or
- Serious uncontrolled cardiac arrhythmia
- Uncontrolled diabetes
- Active or uncontrolled infection
- Interstitial pneumonia or extensive and symptomatic interstitial fibrosis
of the lung.
- Chronic renal disease
- Acute or chronic liver disease (e.g., hepatitis, cirrhosis)
8. Patients unwilling to or unable to comply with the protocol
9. Life expectancy of less than 12 weeks
10. Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study
3. Bevacizumab-Specific Exclusions
1. Inadequately controlled hypertension (defined as systolic blood pressure >150
and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
2. Any prior history of hypertensive crisis or hypertensive encephalopathy
3. New York Heart Association (NYHA) Grade II or greater congestive heart failure
(see Appendix A)
4. History of myocardial infarction or unstable angina within 6 months prior to
5. History of stroke or transient ischemic attack within 6 months prior to study
6. Known CNS disease, brain metastases.
7. Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
8. Symptomatic peripheral vascular disease
9. Evidence of bleeding diathesis or coagulopathy
10. Major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to study enrollment or anticipation of need for major surgical
procedure during the course of the study
11. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to study enrollment
12. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to study enrollment
13. Serious, non-healing wound, ulcer, or bone fracture
14. Urine protein >= 2+ on urinalysis dipstick and >= 1.0 gram on 24-hour urine
15. Known hypersensitivity to any component of bevacizumab
16. History of hemoptysis (bright red blood of ½ teaspoon or more per episode)
within 3 months prior to study enrollment.
17. Current, ongoing treatment with full-dose warfarin.