Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia.
OBJECTIVE
Vascular endothelial growth factor (VEGF) plays an important role in the biology of ovarian cancer (OC). Inhibitors of VEGF suppress tumor growth in OC models. Metronomic chemotherapy, defined as frequent administration of low doses of cytotoxic chemotherapy, suppresses tumor growth, possibly by inhibiting angiogenesis. A phase II trial was conducted to evaluate the antitumor activity and adverse effects of bevacizumab and metronomic oral cyclophosphamide in women with recurrent OC.


METHODS
Patients with measurable disease and prior treatment with a platinum-containing regimen were eligible. Up to two different regimens for recurrent disease were allowed. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks and oral cyclophosphamide 50 mg/d. The primary end point was progression-free survival at 6 months. Plasma levels of VEGF, E-selectin, and thrombospondin-1 were obtained serially.


RESULTS
Seventy patients were enrolled. The probability of being alive and progression free at 6 months was 56% (+/- 6% SE). A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. The most common serious toxicities were hypertension, fatigue, and pain. Bevacizumab-related toxicities included four episodes of gastrointestinal perforation or fistula, two episodes each of CNS ischemia and pulmonary hypertension, and one episode each of gastrointestinal bleeding and wound healing complication. There were three treatment-related deaths. Levels of VEGF, E-selectin, and thrombospondin-1 were not associated with clinical outcome.


CONCLUSIONS
The combination of bevacizumab and metronomic cyclophosphamide is active in recurrent OC. Further study of this combination is warranted.
Garcia
Agustin A
AA
University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. aagarcia@usc.edu
Hirte
Hal
H
Fleming
Gini
G
Yang
Dongyun
D
Tsao-Wei
Denice D
DD
Roman
Lynda
L
Groshen
Susan
S
Swenson
Steve
S
Markland
Frank
F
Gandara
David
D
Scudder
Sidney
S
Morgan
Robert
R
Chen
Helen
H
Lenz
Heinz-Josef
HJ
Oza
Amit M
AM
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002140:California; D002641:Chicago; D003520:Cyclophosphamide / Q000008:administration & dosage; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019040:E-Selectin / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D015996:Survival Rate; D019700:Thrombospondin 1 / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019040:E-Selectin; D019700:Thrombospondin 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D003520:Cyclophosphamide