A Phase II Trial of Gemcitabine Plus Bevacizumab in Patients With Platinum-Resistant Ovarian, Primary Peritoneal or Fallopian Tube Cancer

Inclusion Criteria:

Patients must have platinum-resistant ovarian, primary peritoneal or fallopian tube
cancer.

Patients will be included in the study based on the following criteria:

1. Signed informed consent

2. Age ≥ 19 yrs

3. Advanced, histologically documented ovarian, primary peritoneal, or fallopian tube
cancer

4. Measurable disease with at least one lesion that can be accurately measured in at
least one dimension (longest dimension recorded). Each lesion must be > 20 mm when
measured by conventional techniques, including palpation, plain x-ray, CT and MRI, or
> 10 mm when measured by spiral CT. OR Clinically or radiologically detectable
disease (ascites, peritoneal deposits, mesenteric thickening or lesions that do not
fulfill RECIST for measurable disease). In addition, the subject must have two
consecutive rising pretreatment CA-125 levels that are both > 2x the institutional
upper limit of normal (ULN) and 40.0 IU/ml taken at least 1 week and nor more than 3
months apart.

5. Platinum-resistant or refractory cancer; subjects must not have had a biologic or
chemotherapeutic regimen for treatment of platinum-resistant disease prior to study
entry. Subjects with primary platinum-resistant cancer must have had a tumor
recurrence within 6 months after completing or while receiving a platinum-containing
regimen. These subjects must not have had any other non-platinum-containing regimen.
OR Subjects with secondary platinum-resistant cancer may have had any regimen with
any response and then have had tumor recurrence within 6 months after completing or
while receiving retreatment with a platinum-containing regimen. These subjects must
have received only two prior chemotherapeutic regimens. OR Subjects who receive a
chemotherapeutic regimen as consolidation after a response to a platinum-containing
regimen must have had tumor recurrence within 6 months after completing or while
receiving the consolidation regimen.

6. Life expectancy > 12 weeks

7. ECOG performance status 0 or 1

8. Use of an effective means of contraception (for women of childbearing potential)

9. Clinical laboratory test results: Granulocyte count > 1500/µL; Platelet count >
75000/µL; Hemoglobin > 9g/dL (hemoglobin may be supported by transfusion or
erythropoietin or other approved hematopoietic growth factors; darbopoeitin is
permitted); Serum bilirubin < 1.5 the ULN; alkaline phosphatase, AST, and ALT < 2.5
ULN ( AST, ALT < 5.0 ULN for subjects with liver metastasis); Serum creatinine < 1.5
ULN; International normalized ratio (INR) < 1.5 and activated partial thromboplastin
time (aPTT) < 1.5 ULN (except for subjects receiving anti-coagulation therapy)

Exclusion Criteria:

1. Prior treatment with gemcitabine

2. Three or more prior chemotherapeutic regimens for the management of primary disease

3. Prior treatment with experimental anti-cancer agents within 4 weeks prior to Day 1
(the day the first study treatment infusions are administered)

4. History or clinical evidence of central nervous system or brain metastases

5. Prior treatment with Avastin or other anti-angiogenic agent

6. Uncontrolled hypercalcemia ( >11.5 mg/dL)

7. History of other malignancies within 5 years of Day 1, except for adequately treated
carcinoma in situ of the cervix, ductal carcinoma in situ (DCIS) of breast, basal or
squamous cell skin cancer

8. History of serious systemic disease, unstable angina, myocardial infarction, stroke,
transient ischemic attack,, symptoms of CHF, or unstable symptomatic arrhythmia
requiring medication (subjects with chronic atrial arrhythmia, i.e., atrial
fibrillation, paroxysmal supraventricular tachycardia, are eligible) within 6 months
prior to Day 1 of treatment

9. Known HIV infection

10. Pregnancy or lactation

11. Major surgery, open biopsy, or significant traumatic injury within 4 weeks prior to
Day 1 of treatment, or anticipation of need for major surgical procedure during the
course of the study

12. Inability to comply with study and follow-up procedures

13. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the subject at high risk from treatment
complications

14. Life expectancy of less than 12 weeks

15. 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

16. Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications)

17. Any prior history of hypertensive crisis or hypertensive encephalopathy

18. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see
Appendix E)

19. Known CNS disease

20. Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

21. Symptomatic peripheral vascular disease

22. Evidence of bleeding diathesis or coagulopathy

23. Any patient that the clinician considers at risk for possible GI perforation. This
includes patients with clinical symptoms or signs of GI obstruction or who require
parenteral nutrition, parenteral hydration, or tube feeding, and patients with
evidence of free air not explained by paracentesis or recent surgical procedure.

24. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to study enrollment

25. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to study enrollment

26. Serious, non-healing wound, ulcer, or bone fracture

27. Proteinuria at screening as demonstrated by either Urine protein:creatinine (UPC)
ratio ≥ 1.0 at screening OR Urine dipstick for proteinuria ≥ 2+ (patients discovered
to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour
urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).

28. Known hypersensitivity to any component of bevacizumab

29. Pregnant (positive pregnancy test) or lactating. Use of effective means of
contraception (men and women) in subjects of child-bearing potential